JP2001506258A - Ethylidene derivatives of tricyclic carbapenems - Google Patents

Abstract

Disclosed are novel ethylidene derivatives of tricyclic carbapenems of the formula Iwherein the ring marked C and X have the meaning as in the description, in the form of pure diastereoisomers and in the form of pure geometric isomers. Novel ethylidene derivatives of tricyclic carbapenems of the formula I are used as inhibitors of the action of the enzyme beta-lactamase and/or as antibiotics in human and veterinary medicine. Also disclosed are pharmaceutical formulations for the treatment of bacterial infections of human and animal organisms comprising as an active ingredient a therapeutically effective amount of an ethylidene derivative of tricyclic carbapenems of the formula I in the form of an acid, a pharmaceutically acceptable salt or ester thereof and optionally in a combination with a beta-lactam antibiotic, and usual pharmaceutically acceptable carriers and auxiliary substances.Also disclosed is a process for the preparation of novel ethylidene derivatives of tricyclic carbapenems of the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION                   Ethylidene derivatives of tricyclic carbapenems Technical field   The invention belongs to the field of the pharmaceutical industry and to the pure diastereomer forms and pure Ethylidene derivatives of tricyclic carbapenems in the form of geometric isomers, their preparation PRODUCTION METHOD, PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AND VETERINARY MEDICINE Regarding its use in. Novel Ethylidene Derivative of Tricyclic Carbapenem is β- Used as an inhibitor of lactamase action and / or an antibiotic. Technical issues   Novel, effective due to resistance to various antibiotics and synthetic chemotherapeutics There is always a need to prepare effective anti-infectives. Also, β-lactam antibiotics Of novel inhibitors of the enzyme β-lactamase responsible for resistance to substances It is always required. New Ethylidene Derivatives of Tricyclic Carbapenems Are Enzymes A compound that is an inhibitor of elementary β-lactamase and / or an antibiotic. Conventional technology   Heretofore, carbapenem compounds have been known as effective antibacterial agents. New sub The group's carbapenem compounds are broad inhibitors as inhibitors of the enzymes D, D-peptidase. A novel antimicrobial agent against a range of pathogenic Gram-negative and Gram-positive bacteria Tricyclic carbapenems (first disclosed in EP-A-416953 and EP-A-422596) (A. Perboni et al., Recent Advances in the Chemistry of Antiinfective Agents, Bentley, H.H., Ponsford, R. Ed., The Royal Society of Chemistry, T. . Graham House, Cambridge, 1992, p21 and S.M. Hannesian et al., Bioorg. Med. Chem. Lett., 5, (1995) 2535].   Typical carbapenem compounds with antimicrobial activity are US 5459260, EP-A-502464 No., EP-A-502465, EP-A-502468, EP-A-517065, PCT-WO-94 / 05666, US5372993, US5374630, PCT-WO-94 / 21637, PCT-WO-94 / 21638, PCT-WO -95/03700, PCT-WO-95 / 13278, PCT-WO-95 / 23149, JP 06,166688 and JP No. 08,53459.   Compound 4S, 8S-4-methoxy- (9R, 10R, 12R) -10- (1-hydroxyethyl) -11-oxo- 1-azatricyclo- [7.2.0.0^3,8] Undeca-2-ene [GV104326, ie Sunfetri Nem (sanfetrinem) is an enzyme that is essential for the bacterial growth process. It is a biologically active substance having an action on tidase [E. diModugno, etc., Anti microb. Agents Chemother., 38 (1994), 2362].   For all of the conventionally disclosed tricyclic carbapenem compounds, β-lactam There is no data on the inhibitory effect of these species on enzymes. Therefore, Ming has a completely novel structure and has the property of inhibiting the enzyme β-lactamase And a novel ethylidene derivative of a tricyclic carbapenem compound. This property Does not reduce its important antimicrobial activity. Technical solution   The present invention provides a compound of formula I: ｛Wherein the C is fused to the basic carbapenem nucleus at positions 3 and 4 The ring is a 5, 6 or 7 membered ring, wherein 1. One or more carbon atoms in the ring labeled C are the same or It can be mono- or di-substituted with the following substituents, which can be different:   a) hydrogen atom,   b) a saturated alkyl chain having 1 to 20 carbon atoms; (Eg, methyl, ethyl, n-propyl, n-butyl) or Divergent (e.g. isopropyl, s-butyl, isobutyl, isoamyl, ter t- Butyl) and each of the members of the chain is a substituent such as May be mono- or di-substituted; that is, halo (fluoromethyl, trifluoromethyl, Like 2-chloroethyl), hydroxy (hydroxymethyl, 2-hydroxyethyl ), (C₁-C_Four) Alkyloxy (methoxymethyl, 2-methoxyethyl ), Mercapto and (C₁-C_Four) Alkyl mercapto (mercaptomethyl, 2- (Like methyl mercaptoethyl), (C₁-C_Four) Alkanesulfonyl (methanesulfur Like honylmethyl), amino, (C₁-C_Four) Alkylamino and di- (C₁-C_Four) Al Killamino (2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl ), Alkyleneamino [2- (1-piperidinyl) ethyl, 1-pyrrolidinyl Methyl-like), guadinino (like guadininomethyl), unsubstituted N¹-mono , N^Three-Things, N¹, N^Three-J and N^Three, N^Three-Ji- (C₁-C_Four) Formamidino (iminomethylamido) Like methyl, 2- (dimethylaminomethyleneamino) ethyl), aromatic or Teroaromatic 5 or 6 ring (like phenyl, furyl, 2-pyridyl), (C₁-C_Four) Alkyloxycarbonyl (like carboethoxymethyl), cyano (2-cy Like ethyl, oxo (acetyl, propionyl, 2-oxopropyl) Especially) may be mono- or di-substituted by   c) an unsaturated alkyl chain having 1 to 20 carbon atoms; Straight chain and having a double bond or a triple bond (for example, vinyl, propenyl, Ryl, ethynyl, propargyl) or branched at any position and double Having a bond or a triple bond (eg, 2-propenyl); Thus, each of the members of the chain has the following substituents: halo, hydroxy, (C₁-C_Four) Al Killoxy, thio and (C₁-C_Four) Alkylthio, (C₁-C_Four) Alkanesulfonyl, ami No, (C₁-C_Four) Alkylamino and di- (C₁-C_Four) Alkylamino, aromatic or hetero Aromatic 5- or 6-rings (like phenyl, furyl, 2-pyridyl), (C₁-C_Four) Al Mono- or di-substituted by substituents such as killoxycarbonyl, cyano, oxo; Can be;   d) 3-7 membered saturated or partially unsaturated cycloalkyl groups (e.g. cyclopropyl A group from ropyl to cycloheptyl, cyclohex-1-enyl); Containing one or more of sulfur, nitrogen or nitrogen atoms (eg 2-tetrahydro H Ranyl, 1-piperidinyl, 1-pyrrolidinyl) and the ring structure Each of the members is halo, hydroxy, (C₁-C_Four) Alkyloxy, thio and (C₁-C_Four) Al Kirchio, (C₁-C_Four) Alkanesulfonyl, amino, (C₁-C_Four) -Alkylamino and Di- (C₁-C_Four) Alkylamino, (C₁-C_Four) Alkyloxycarbonyl, cyano, oki May be mono- or di-substituted by substituents such as oxo;   e) 5- or 6-membered aromatic or heteroaromatic rings (eg phenyl, furyl, 2-pyri Jill),   f) hydroxy, (C₁-C_Ten) Alkyloxy (e.g., methoxy, ethoxy, n- Loxy, isopropoxy, tert-butoxy, cyclohexyloxy), mono or Is disubstituted- (C₁-C_Ten) Alkyloxy (eg, 2-hydroxyethyloxy, 2,3-di Hydroxyprop-1-yloxy, 2-methoxyethyloxy, fluoromethylo Xy, aminoethyloxy, 2-dimethylaminoethyloxy), acyloxy ( For example, formyloxy, acetyloxy, benzoyloxy, ethoxycarboni Ruoxy, allylcarbonyloxy), mono, di or tri- (C₁-C_Four) Alkyl Loxy (eg, trimethylsilyloxy, tert-butyldimethylsilyloxy ) Group,   g) Mercapto, (C₁-C_Ten) Alkyl mercapto (eg, methyl mercapto, Thiomercapto), mono- or di-substituted- (C₁-C_Ten) Alkyl mercapto (for example, 2- Droxyethyl mercapto, 2,3-dihydroxyprop-1-ylmercapto, Toxiethyl mercapto, 2-mercaptoethyl mercapto, 2-methylmercapto Ethyl mercapto, 2-aminoethyl mercapto, 2-dimethylaminoethyl merka ), An acylmercapto group (eg, acetylmercapto),   h) amino, (C₁-C_Four) Alkylamino and di- (C₁-C_Four) Alkylamino [e.g. Methylamino, dimethylamino, 2-hydroxyethylamino, bis (2-hydroxy (Shiethyl) amino, aminoethyloxy, 2-dimethylaminoethyloxy, 2-A Minoethylamino, 2-piperidinoethylamino), acetylamino, allyloxy Cicarbonylamino, iminomethylamino, N-methylaminomethyleneamino, N, N-dimethylaminomethyleneamino, guanidino, cyanoguanidino, methylene Anidino group,   i) a halo atom (eg, fluoro, chloro, bromo, iodo),   j) azide, nitro, cyano, (C₁-C_Four) Alkyloxycarbonyl group (eg, Carbomethoxy, carboethoxy),   k) (C₁-C_Four) Alkanesulfonyl groups (eg, methanesulfonyl, ethanesulfonyl) Nil); 2. One or more carbon atoms in the ring labeled C are> C^*= CR¹R^TwoForm of With a substituted or unsubstituted alkyl linked to the ring labeled C via a double bond. Can be substituted with^*Represents a carbon atom in the ring with the symbol C, and = represents a ring. Represents an external double bond, and represents a substituent R¹And R^TwoAre the same or different One means:   a) a hydrogen atom; thus, the substituent is methylene;   b) an unsubstituted saturated alkyl chain having 1 to 20 carbon atoms; Kill chains are straight chain (eg, ethylidene, n-propylidene, n-butylidene, isopropylidene). ) Or branched at any position (eg, 2,2-dimethylpro Pyridene);   c) an unsubstituted unsaturated alkyl chain having 1 to 20 carbon atoms; The alkyl chain has a double bond or a triple bond, and is linear or can be separated at any position. Can be diverse (eg, vinylidene, arylidene);   d) 3-7 membered saturated or partially unsaturated unsubstituted cycloalkyl or heteroaryl Reels (for example, groups from cyclopropylmethylene to cycloheptylmethylene) );   e) 5- or 6-membered aromatic or heteroaromatic rings (eg benzylidene, diphenylene) A group such as rumethylene),   f) a saturated or partially unsaturated substituted alkyl chain or a 3-7 membered substituted carboxy In this case, any carbon atom of the alkyl chain or the carboxyl ring is halo, Roxy, (C₁-C_Four) Alkyloxy, (C₁-C_Four) Alkylthio, (C₁-C_Four) Alkansul Honyl, amino, (C₁-C_Four) Alkylamino, di- (C₁-C_Four) Alkylamino, (C₁-C_Four) Mono- or di-substituted by a substituent such as alkyloxycarbonyl, cyano, oxo These groups are, for example, hydroxyethylidene, methoxyethylidene or Consisting;   g) hydroxy, (C₁-C_Four) Alkyloxy, acyloxy, mercapto, (C₁-C_Four ) Alkyl mercapto, amino, (C₁-C_Four) Alkylamino, di- (C₁-C_Four) Alkyl Amino and acylamino groups; these groups are for example hydroxymethylene, methoxy Methylene, dimethoxymethylene, dimethylaminomethylene, acetylaminomethyl Consisting of groups such as len groups;   h) Nitro, cyano, (C₁-C_Four) Alkyloxycarbonyl groups; thus, substituents Is, for example, dicyanomethylene, bis (carbomethoxy) methylene, carbethoxy Simethylene;   Substituent R¹And R^TwoIs a linked alkylene chain that is closed to form a ring (CH_Two) n (n = 2-7) can also be represented, and any methylene (CH_Two) Members are oxa (-O-), thia (-S -), Imino (-NH-) or (C₁-C_Four) Can be substituted by alkylamino; This substituent can be cyclopentylidene, cyclohexylidene, 2- (1,3-dioxacyclo Lopentylidene); 3. One or more carbon atoms in the ring labeled C may be Can be substituted with a heteroatom (oxo, thioxo, hydroxyimino, (C₁-C_FourA) Like ruquilimino and acylimino]; 4. One or more carbon atoms in the ring labeled C form a spiro compound. To form a ring which is closed to form a ring; Thus, ring members can be oxygen, sulfur and nitrogen atoms in addition to carbon atoms (D Like Tylene, 1,3-propylene, 1,5-pentylene, ethylenedioxy); 5. One or more carbon atoms in the ring labeled C are replaced by oxygen atoms. Can be; 6. One or more carbon atoms in the ring marked C are replaced by sulfur atoms. This sulfur atom can be mono- or dioxidized to form a sulfoxide or sulfoxide. May form; 7. One or more carbon atoms in the ring labeled C are> N^*-R^ThreeIn the form of A nitrogen atom which can be replaced;^*Is in the ring labeled C Represents a nitrogen atom, R^ThreeMeans the following:   a) a saturated alkyl chain having 1 to 20 carbon atoms; this unsubstituted saturated alkyl chain Is linear (eg, methyl, ethyl, n-propyl, n-butyl) or at any position (E.g., isopropyl, s-butyl, isobutyl, isoa Mill, tert-butyl), and each of the members of the alkyl chain is , The following substituents: halo (fluoromethyl, trifluoromethyl, 2- Chloroethyl), hydroxy (like hydroxymethyl), (C₁-C_Four) Alkyloxy (like 2-methoxyethyl), (C₁-C_Four) Alkylthio (methyl (Like mercaptoethyl), (C₁-C_Four) Alkanesulfonyl (methanesulfonyl Like methyl), amino, (C₁-C_Four) Alkylamino, di- (C₁-C_Four) Alkylami No (like 2-aminoethyl, 2-methylaminoethyl, 2-dimethylaminoethyl) , Aromatic or heteroaromatic 5 or 6 tricyclic (such as phenyl, furyl, 2-pyridyl) ), (C₁-C_Four) Alkyloxycarbonyl (like carboethoxymethyl), Cyano (like cyanoethyl), oxo (acetyl, propionyl, 2-oxo Propyl), imino (iminomethyl, aminoiminomethyl, aminosia As in the case of neuminomethyl).   b) an unsubstituted saturated alkyl chain having 1 to 20 carbon atoms; The kill chain is straight and has a double bond (eg, vinyl, propyl, allyl) Or a compound having a triple bond (eg, ethynyl, propargyl) Is branched at any position and has a double bond or a triple bond (e.g., 2- Propenyl);   c) 3-7 membered saturated or partially unsaturated unsubstituted cycloalkyl or heteroaryl Reels (for example, groups from cyclopropyl to cycloheptyl, cyclohex-1-yl Enyl, 4-piperidinyl);   d) 5 or 6 unsubstituted aromatic or heteroaromatic rings (eg phenyl, furyl , 2-pyridyl);   e) Cyano, (C₁-C_Four) Alkyloxycarbonyl (e.g., carbomethoxy, Ruboethoxy), aminocarbonyl, (C₁-C_Four) Alkylaminocarbonyl, (C₁− C_Four) Groups such as alkanesulfonyl (methanesulfonyl);   X means: 1. A hydrogen atom; in this case, the compound of formula I is a carboxylic acid; In the heart (basic centre), the hydrogen atom is connected to the molecule as a proton, The boxyl group is in the form of an anion, such as a carboxylate, and the compound of formula I is In the form of zwitterions; 2. An alkali metal; in this case, the compound of formula I is an alkali metal salt (e.g. Lithium, sodium carboxylate, potassium carboxylate); 3. Alkaline earth metal; in this case, the compound of formula I Alkaline earth metal salts in which two carboxylate anions are present (eg, Sodium dicarboxylate); 4. Mono-, di- or tri-substituted, non-ammonium ions or protonated forms A cyclic or cycloaliphatic amine or some other nitrogen base in protonated form; In this case, the compound of the formula I is obtained by reacting a carboxylic acid with ammonia or an amine (trimethylamido). , Triethylamine, N, N'-dibenzylethylenediamine, ethanolamine , Diethanolamine, triethanolamine, dicyclohexylamine, 2-pi Peridinyl) or amidine [eg, 1,8-diazabicyclo [5,4,0] undec-7-ene , 1,5-diazabicyclo [4,3,0] non-5-ene, 3,3,6,9,9-pentadimethyl-2,10-di Azabicyclo [4,4,0] undec-7-ene] or guanidine (eg, guanidine, Anoguanidine) or some other nitrogen base (eg, 4-dimethylaminopyridine , Imidazole). 5. A quaternary ammonium ion; in this case, the compound of formula I Ammonium carboxylate (eg, tetrabutyl ammonium carboxylate G); 6. Group R^FourIn this case, the compound of formula I is in the form of an ester;^FourIs   a) (C₁-C₂₀) Alkyl (eg methyl, ethyl, tert-butyl), (C₁-C₂₀A) Alkenyl (eg, allyl), substituted alkyl [eg, (C₁-C_Four) Alkyloxyal Kill, (C₁-C_Four) Alkylthioalkyl, phenethyl, 2,2,2-trichloroethyl, 2 -Oxo-5-methyl-1,3-dioxolen-4-yl) methyl, benzyl, p-methoxy Benzyl, p-nitrobenzyl, o-nitrobenzyl, bis (methoxyphenyl) methyl , 3,4-dimethoxybenzyl, benzohydryl, trityl, 2-trimethylsilyl Ethyl], substituted silyls (eg, trimethylsilyl, tert-butyldimethylsilyl ), Whether the group is selected from taridyl or the like;   b) The following formula [Wherein, R^FiveRepresents hydrogen, lower alkyl having 1 to 4 carbon atoms,⁶Is water Element, alkyl, cycloalkyl, alkoxy, cycloalkoxy, cycloalkyl Represents alkylalkyl, alkenyloxy, phenyl). Thus, the compounds of formula I are a class of cephalosporin antibiotics as prodrugs Known biodegradable esters [eg, 1-pivaloylmethyl, 1-pivaloy Ethyl, acetoxyethyl, 1-acetoxyethyl, 1-methoxy-methylethyl Carbonyloxymethyl, 1- (1-methoxy-1-methylethylcarbonyloxy) Tyl, 1-benzoyloxyethyl, 1- (isopropoxycarbonyloxy) ethyl , Cyclohexyloxy-carbonyloxymethyl ester]]] is represented by To an ethylidene derivative of a tricyclic carbapenem.   The present invention relates to a new class of pure diastereomeric and pure geometric isomers. It relates to an ethylene derivative of a tricyclic carbapenem of the general formula I. Compounds of formula I are of formula I The methyl group in the ethylidene substituent at the 6-position of the carbapenem ring of the compound of formula If configured as (Z) or (E) around the bond, Both consist of two pure geometric isomers and are formed at the point of contact with the new ring The asymmetric center at position 4 is arranged as (R) or (S) so that at least two pure Consists of smart diastereomers. In FIG. 1 and all other figures, the thick line connection (bol dbond) represents a position above the paper surface, and a broken line represents a position below the paper surface. Symbol (R ) Or (S) is the type of the ring with the symbol C and the substituent attached to the ring with the symbol C And the Cahn-Ingold-Prelog arrangement rule (Cahn et al., Experientia 12 (195 6) 81].   The configuration at the 5-position at the 4 and 5 ring contacts of the compound of general formula I is always the same. And is always below the page, and the symbol (R) or (S) is It is determined according to the log arrangement rule. FIG. 1: Form as pure geometric isomer and as pure diastereomer, Novel Ethylidene Derivatives of Tricyclic Carbapenems   The compounds of formula I below are inhibitors and / or antibiotics of the enzyme β-lactamase. Are particularly important: − (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8] C   Ndeca-2-ene-2-carboxylic acid, a pharmaceutically acceptable salt or ester thereof − (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.O.33.8] C   Ndeca-2-ene-2-carboxylic acid, a pharmaceutically acceptable salt or ester thereof − (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2   .0.0^3,8] Undeca-2-ene-2-carboxylic acid, its pharmaceutically acceptable salt or d   Steal − (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.0.   0^3,8] Undeca-2-ene-2-carboxylic acid, its pharmaceutically acceptable salt or S   Tell − (4S, 8S, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatricyclo   [7.2.0.0^3,8] Undec-2-en-2-carboxylic acid, a pharmaceutically acceptable salt or   Is an ester − (4R, 8R, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatricyclo   [7.2.0.0^3,8] Undec-2-en-2-carboxylic acid, a pharmaceutically acceptable salt or   Is an ester − (4S, 8S, 9R) -4-methoxymethyl-10-[(E) -ethylidene] -11-oxo-1-azatri   Cyclo [7.2.0.0^3,8] Undec-2-en-2-carboxylic acid, its pharmaceutically acceptable   Salt or ester − (4R, 8R, 9R) -4-methoxymethyl-10-[(E) -ethylidene] -11-oxo-1-azatri   Cyclo [7.2.0.0^3,8] Undec-2-en-2-carboxylic acid, its pharmaceutically acceptable   Salts or esters.   The compound of formula I in the form of an acid and its pharmaceutically acceptable esters is expressed in grams Bactericidal activity against positive and / or gram negative bacteria or other infectious agents (bacteriostatic action) and an antibacterial agent having bactericidal activity (bactericide action) And used for the prevention and treatment of infectious diseases in humans and animals. Follow Thus, the present invention provides a compound of formula I and a pharmaceutically acceptable salt or ester thereof, Humans caused by Gram-positive and / or Gram-negative bacteria and other microorganisms And for use in the treatment of bacterial diseases in animals.   Compounds of the formula I in the form of an acid and its pharmaceutically acceptable esters are, in particular, Pharmaceutical compositions or other β-lactones such as penicillin and cephalosporins As an inhibitor of the enzyme β-lactamase in a pharmaceutical composition in combination with tam antibiotics Is also used. Therefore, effective against microorganisms resistant to β-lactam antibiotics Antibacterial action can also be achieved. The mechanism of action of the enzyme β-lactamase has been Has been studied [J. Knowles, Acc. Chem. Res. 18, (1985) 97] The amide bond of β-lactam antibiotics is hydrolyzed, resulting in the enzyme D, D-peptide This ability can be described as a loss of its ability to inhibit dase; This is the condition for the antibiotic to act as an antibiotic. Enzyme β-lactamer The inhibition process of zeolites occurs in two stages. The first step is acylation, where the acyl Between the β-lactam inhibitor at the Ser70 site in the protein sequence Tetrahedro Complex is formed, which causes the enzyme to act on antibiotics. This results in a blocade of the active site. The second step is deacylation, which Is a covalent bond between water and amino acid residues in the active site of the enzyme β-lactamase It occurs by action on the drug-enzyme complex. The overall suppression process is the same Resembles the process by which amino acids degrade β-lactam antibiotics (the main difference is that Process and the kinetics of the second process only), thus the β-lactam The structures of antibiotics and inhibitors of the enzyme β-lactamase are similar.   Most of the antibiotics of the penum, carbapenam, cephem and carbacephem types Characteristically, these compounds have an acylamino group or a 1-hydroxyethyl group, Positions (penam) and 7 (cephem) are substituted, but the enzyme β-lactamase To exhibit a relatively low inhibitory action. In addition, tricyclic carbapenam (EP- A-0422596), and similarly substituted compounds from the field of Heretofore, only antibiotic activity has been known. These systems Position 6 must be specifically substituted in order to exhibit the inhibitory effect of β-lactamase It is shown that 6-ethylidene-substituted carbapenam is carbapenam An available system because it can be obtained from intermediates that are also used in the synthesis of antibiotics It was recognized. Conventionally, among these compounds, inhibitors of the enzyme β-lactamase Is not known to act as a molecule, but molecular modeling g) methods, ie, inhibitors of the enzyme β-lactamase used in clinical practice, Calculate and compare electron density of fem type β-lactamase substrate Method (D. Kocjan and T. Solmajer, QSAR and Molecular Modeling, F. Senz , J. et al. Ginaldo and F.S. Monant Editing, Computational Tools and Biological Applic ations, Barcelona, Prous Science Publishers, 1995, pp335-337), Formula I Electron density of the compound of formula (I) and its pharmaceutically acceptable salts or esters Distribution is appropriate for its inhibitory effect on the enzyme β-lactamase Was done. Surprisingly, the compounds of the formula I according to the invention inhibit the enzyme β-lactamase Active as an agent, and therefore, with known carbapenem antibiotics described in the literature. Were found to be different. The results of testing the inhibitory activity of the compounds of formula I also indicate Has been confirmed to inhibit β-lactamase. Determination of the inhibitory effect of compounds of formula I on the enzyme β-lactamase   The inhibitory action of the compounds of the formula I is determined by standard methods (Bush, K. and Aykes, R.B. f Enzymatic Analysis, 3rd edition, Vol. 4, p 280, Verlag Chemie GmnH, Weinheim , 1984). This method uses the enzyme β-derived from E. coli EC3.5.2.6. The catalysis of lactamase is measured by spectrophotometric analysis (at 495 nm band). Consisting of As a substrate, the broadest range of susceptibility and sensitivity (sen nitrocefin ((7R) -3-[(E) -2,4-dinitros) [Tyryl] -7- (2-thienylacetamido) -3-cephem-4-carboxylic acid]. Measurement of Nitrocefin Hydrolysis in the Presence of the Inhibitor of the β-Lactamase Enzyme Was. Hydrolysis of β-lactamase of E. coli 3.5.2.6. In the presence of inhibitors Experimental data:   The concentration of the substrate (nitrocefin) was 190 μmol / l.   The standard concentration of the test inhibitor was 100 μmol / l. 50% or more enzyme inhibition If reduced, the test is performed at lower test inhibitor concentration, ie, 100 μmol / l, 1 Performed at 0 μmol / l and 0.1 μmol / l.   The concentration of the reference inhibitor, sulbactam and clavulanic acid should be It was the same as the concentration of the agent.   Table 1: E. coli against the substrate nitrocefin at various inhibitor concentrations (%)         3.5.2.6. Inhibition of the hydrolytic action of the enzyme β-lactamase Symbol explanation:   a ... (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8]       Sodium undeca-2-ene-2-carboxylate   b ... (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8 ]       Sodium undeca-2-ene-2-carboxylate   c ... (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.       0.0^3,8] Sodium undeca-2-ene-2-carboxylate   d ... (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.       0.0^3,8] Sodium undeca-2-ene-2-carboxylate   e ... (4S, 8S, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatrisic       B [7.2.0.0^3,8] Sodium undeca-2-ene-2-carboxylate   f ... (4R, 8R, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatrisic       B [7.2.0.0^3,8] Sodium undeca-2-ene-2-carboxylate   g ... (4S, 8S, 9R) -4-methoxymethyl-10-[(E) -ethylidene] -11-oxo-1-azato       Licyclo [7.2.0.0^3,8] Sodium undeca-2-ene-2-carboxylate   h ... (4R, 8R, 9R) -4-methoxymethyl-10-[(E) -ethylidene] -11-oxo-1-azato       Licyclo [7.2.0.0^3,8] Sodium undeca-2-ene-2-carboxylate   Accordingly, the present invention relates to a compound of formula I, a pharmaceutically acceptable salt or ester thereof. For use as an inhibitor of the enzyme β-lactamase in human and veterinary medicine And   The present invention further provides a therapeutically effective amount of a compound of Formula I as an active ingredient in the presence of an acid Is in the form of its pharmaceutically acceptable salt or ester, optionally β-lactam Contained in combination with raw materials, and further used in human and veterinary medicine for oral, parenteral, rectal, A pharmaceutically acceptable carrier for topical, ocular, nasal or genital-urinary administration; and Used to treat human and animal infections containing other pharmaceutically acceptable auxiliary materials. A pharmaceutical composition for use.   The parenteral pharmaceutical composition of the present invention comprises a suspending agent, a stabilizing agent, a dispersing agent and / or a preservative. Together with auxiliary substances such as oily carriers or water suspensions, emulsions or dispersions. The powder may be stored in ampoules in the form of, or with, It is stored in a closed container in the form of a powder, and its contents must be removed before use, solvent and most In this case, dissolve in water containing no pyrogen. The parenteral pharmaceutical composition of the present invention It can be administered intravenously or intramuscularly.   The pharmaceutical composition of the present invention comprises syrup, gum arabic, gelatin, sorbitol, Binders such as lagant and polyvinylpyrrolidone, lactose, saccharo Such as sesame, corn starch, calcium phosphate, sorbitol and glycine Filler, magnesium stearate, talc, polyethylene glycol and silicone Lubricants such as mosquitoes, disintegrants such as potato starch and sodium lauryl sulfate Tablets, capsules, pastilles, pills, granules, powders with wetting agents such as It can be used orally in the form of a solid preparation such as Tablets and granules follow known methods. Can be coated with an appropriate coating. The oral pharmaceutical composition of the present invention comprises an antioxidant , Oil preservatives, binders, wetting agents, lubricants, thickeners, fragrances and fragrances It can also be used in liquid form, such as a suspension, solution, emulsion or syrup. solid And liquid formulations are prepared according to generally known methods applicable to the preparation of pharmaceutical compositions. Can be made.   The pharmaceutical composition of the present invention may be used in combination with conventional carriers for human and veterinary applications and other pharmaceuticals. It can also be used in the form of suppositories containing pharmaceutically acceptable auxiliary substances.   Suitable antibiotics optionally used in the pharmaceutical compositions of the present invention include β-lactam Some beta-lactamases, as well as antibiotics that are degraded by mase Is a highly resistant antibiotic. Benzylpe as penicillin Nicilin, phenoxymethylpenicillin, ampicillin, amoxicillin, carbe And cephalosporin. , Cefaclor, cefadroxyl, cefpyramide, ceftriaxone, cefuki A shim or the like can be used. In the pharmaceutical composition, the acid form or pharmaceutically acceptable When a compound of formula I in the form of a salt or ester is combined with another antibiotic, The weight ratio of the compound of I or a pharmaceutically acceptable salt or ester thereof to the antibiotic is 10: 1 to 1:20 and the amount is 0.1 mg to 1000 mg.   In the pharmaceutical composition of the present invention, the acid form or the pharmaceutically acceptable salt or ester The amount of the compound of formula I in the form is from 0.05 to 100 mg of active ingredient per kg of body weight of the animal, preferably More specifically, the active ingredient is 0.1 to 40 mg / kg of animal body weight. The pharmaceutical composition of the present invention It may be administered one to four times daily depending on the route of administration and the patient's state of health.   The invention further relates to a process for preparing the novel compounds of the formula I.   Compounds of formula I have the formula II (Where R⁷Easily removes alkyl, benzyl and 4-nitrobenzyl groups The ring denoted by the symbol C represents the resulting ester protecting group and is as defined for compounds of formula I The same compound as described above) has been described in the literature for tricyclic carbapenems. According to a novel process not shown, the process of conversion to the compound of formula I in three steps Can be prepared. Step 1   In step 1, the hydroxyl group of the compound of formula II is more suitably removed. Which converts to a more easily leaving group to form a compound of formula III; And the group R⁸Can be the following groups:   An acyl group from an aliphatic acid, usually an aliphatic acid having 1 to 10 carbon atoms; Preferably R⁸Means an acetyl group;   An alkanesulfonyl group from an alkanesulfonic acid;⁸Is 1 to 10 Refers to an alkanesulfonyl group having the following carbon atoms: Preferably may have one or more halo groups such as fluoro as substituents; Preferably, R⁸Is methanesulfonyl, ethanesulfonyl, fluoromethanesulfur Fonyl, means trifluoromethanesulfonyl;   -Arene sulfonyl groups from arene sulfonic acids;⁸Is one or It may have further substituents, and preferably (of p-toluenesulfonyl Benzenesulfonyl or heteroarene having a substituent at the para-position Means a heteroarenesulfonyl group from sulfonic acid;⁸Ha Norin-8-sulfonyl is meant.   The conversion of a compound of formula II to a compound of formula III can be best performed in two ways, It does not exclude other methods described in the literature. The reaction is -78 ° C to reflux of the solvent The reaction is carried out at a temperature, preferably between -20 ° C and room temperature, and the reactants are most often -20 ° C to 0 ° C. To the reaction mixture at a temperature of, after which the temperature is raised to room temperature. The reaction is the last Complete immediately after the addition of the reactants, at the latest in 24 hours, usually in 10-120 minutes Complete.   According to the first method, the conversion of the compound of formula II to the compound of formula III is inert. The reaction is performed using a reactive acid derivative in an organic solvent in the presence of a base. Reactive acid derivative Is a reactive derivative of a carboxylic acid or a sulfonic acid, for example, an acid halide R⁸ X '(where X' represents halogen, preferably chlorine) may be used; preferred The reactants are methanesulfonyl chloride, p-toluenesulfonyl chloride, acid-free Fish (R⁸)_TwoO, preferably acetic anhydride, trifluoromethanesulfonic anhydride. You. The base may be a mono-, di- or tri-substituted alkylamine, preferably Tylamine, diethylisopropylamine, N, N, N ', N'-tetramethylethylenedi Amine or 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo Amidines such as [4.3.0] non-5-ene, or pyridine, imidazole, Organic nitrogen bases such as aromatic bases such as methylaminopyridine may be used. As the inert organic solvent, ether, preferably tetrahydrofuran, dioxane , Aromatic hydrocarbons such as benzene and toluene, pyridine and acetonitrile Inert solvents such as heterocyclic compounds may be used; preferably, inert organic solvents are used. Chlorinating solvents, preferably dichloromethane, can be used as agents. Inert organic solvent Such as compounds, N, N-dimethylformamide and N, N-dimethylacetamide Sometimes compounds which simultaneously participate in the reaction and action of the reactive acid derivative can also be used.   According to a second method, the reaction of converting a compound of formula II to a compound of formula III is preferred. Or the acid R in the same organic solvent as described in the first method.⁸Done using OH The acid is converted to a compound of formula III using a condensing agent (reactant to remove water). To the hydroxy group at the position. As the condensing agent, N, N'-carbonylimidazo Diphenylphosphoryl azide, diphenylphosphoryl cyanide, carbodi Imides such as dicyclohexylcarbodiimide, N-ethyl-N '-(3-dimethylamido Nopropyl) -carbodiimide, diazacarboxylate in the presence of phosphine (Mitsunobu's reaction, O. Mitsunobu, Synthesis1981, 1), preferably triphenylpho Diethyldiazacarboxylate in the presence of sphing may be used. This way In addition, other methods suitable for removing water may be used. Step 2   In the second step of the conversion of the compound of formula II to the compound of formula I, Substituent R of compound⁸Is removed by a base-catalyzed removal operation to give the compound of formula IV Get things. In this reaction, the base is an inorganic base (eg, an alkali metal charcoal). Acid salts), organic bases such as alkali metal salts of alcohols (eg sodium Toxide, sodium ethoxide, potassium tert-butoxide), amide Potassium metal salts (e.g. lithium bis (trimethylsilyl) amide, lithium diiso Propylamide], an alkyl metal (eg, butyllithium), an aryl metal (eg, Phenyllithium), organic amines (eg, triethylamine, ethyldiiso Propylamine, tetramethylethylenediamine), amidine (eg, 1,8-dia Zabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene May be used; a base of the amidine type is converted to a non-nucleophilic, soluble in aprotic organic solvent. It is preferably used as a strong base in the reaction. As the solvent, an inert organic solvent , For example, alcohols (eg, methanol, ethanol, tert-butanol, Amides, alkyl metals and aryl metals are used when they are used as bases. Hydrocarbons such as aromatic hydrocarbons (eg, benzene, toluene) , Ketone (eg, acetone), ester (eg, ethyl acetate), acetonitrile , Amides (eg, N, N-dimethylformamide, N, N-dimethylacetamide, Samethylphosphonic triamide), dimethyl sulfoxide, preferably tetra Ethers such as hydrofuran and dioxane and dichloromethane, chloroform A chlorinated solvent such as chloroethane is used. The reaction is at -78 ° C to the reflux temperature of the solvent. Degree, preferably at -20 ° C to room temperature. The reaction is between 5 minutes and 48 hours, often Performed for 1-6 hours.   The reaction of obtaining a compound of formula IV from a compound of formula II involves isolating the compound of formula III. Can be implemented directly with or without. In these cases, the group R⁸O is a compound of formula III during the following operation Spontaneously detached from:   -The compound of formula II under the influence of the base used in the reaction with the reactive acid derivative During the reaction to convert to the compound of III;   Conversion of a compound of formula II to a compound of formula III using a reactive acid derivative During operation, or during the operation of isolating the compound of formula III (in this case, Separation occurs in the absence of a base);   -A compound of formula III under the influence of a chromatographic support (e.g. silica gel). During purification of the product by chromatography.   The conversion of a compound of formula II to a compound of formula IV does not involve the synthesis of a compound of formula III Can be done directly. In this case, water is removed from the site of the hydroxy group of the compound of formula II. Let Desorption of water was carried out under the conditions of Mitsunobu (O. Mitsunobu, Synthesis, 1981, 1), Diazaka Using a ruboxylate, preferably diethyldiazacarboxylate, It is carried out in the presence of a fin, preferably triphenylphosphine. Reaction is -78 ° C The reaction is carried out at the reflux temperature of the solvent, preferably at -20 ° C to 30 ° C. Reaction is the last reactant It can be completed immediately after addition of and at the latest in 24 hours, usually 10-120 minutes.   The group R from the compound of formula III⁸O or water from the compound of formula II is The methyl group in the ethylidene substituent at position 6 of the bapenem ring is a double bond as (Z) or (E) And, in many cases, the (E) isomer is prevalent Desorb as follows.   In the process of preparing compounds of formula IV, the point of attachment to the ring labeled C is A new asymmetric center is formed at the 4-position of the carbapenem ring of the compound of formula IV The two diastereomers 4- (R)-and 4- (S)-are also formed. Individual diastereos Can be separated by chromatographic purification on a chromatographic support. You.   Synthetic process for obtaining a compound of formula IV from a compound of formula II via a compound of formula III Is carried out using isomers which have already been separated to give two compounds in the compound of formula II May already be separated. For certain reasons (eg poor splitting) If the diastereomers of the compound of formula II cannot be separated, the individual The diastereomers are separated from the diastereomer mixture of a compound of formula III or IV Note It can also be obtained in the subsequent steps of the same method as the above method.   Both geometric isomers can be obtained by chromatographing the isomer mixture of the compound of formula IV on silica gel. It is isolated by purification by chromatography.   Synthetic routes disclosed for preparing compounds of formula IV are other known from the literature. It does not exclude the method. Step 3   Final step of converting a compound of formula II via a compound of formula IV to a compound of formula I In the formula, the substituent COOR at the 2-position of the carbapenem ring of the compound of the formula IV⁷From a specific The ester protecting group R according to generally known methods for removing protecting groups⁷ Is removed. For example, an allyl group may be a phosphine (preferably a triphenylphosphine). ), And an alkali metal cation (preferably 2-ethylhexanoic acid) Under the conditions under which the alkali metal salt of the compound is added, a Pd (O) catalyst [preferably tetrakis [Riphenylphosphine) palladium (O)]. Ben Jil and 4-nitrobenzyl groups are alkali metal cation donors (TW Green, Pro. tective Groups in Organic Synthesis, John Wiley & Sons, New York, p 191) by catalytic hydrogenation; in the presence of palladium on a catalyst as a catalyst. Use a material that carries a medium (for example, 10% palladium on activated carbon) It is also preferable to use sodium hydrogencarbonate as the alkali metal cation. Or the use of potassium; the product of the two conversion reactions is A compound of formula I that is a metalloid. Removal of protecting groups without the presence of cations When removed, the compound of formula I in the acid form, in which X represents hydrogen, is isolated. The salt is prepared by neutralization or reprecipitation according to methods known from the literature. You. Protecting group R⁷Is a nitrogen base such as ammonia, amine (eg, trimethylamido) , Triethylamine, N, N-dibenzylethylenediamine, ethanolamine, Diethanolamine, triethanolamine, dicyclohexylamine, 2-pipe Lysinyl), amidines (eg, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene), 3,3,6,9,9-pentadimethyl-2,10-dia Zabicyclo [4.3.0] non-5-ene), guanidine (eg guanidine, cyanogua Nidin) and other nitrogen bases (eg, 4-dimethylaminopyridine, imidazole) In the compound of formula I thus obtained, X is Represents a toned nitrogen base.   There is a substituent protected by a well-known protecting group in the ring labeled C of the compound of the formula IV. In some cases, these protecting groups are removed with the reagents described in the description for step 3. Should be removed first before step 3 by well-known deprotection methods, except where .   The compounds of the formula I in the acid form or in the form of a salt (X represents an alkali metal) are known from the prior art. By the process, it can be converted to a biologically acceptable ester of formula I, in which case , X is an organic alkyl group, especially CHR^FiveOCOR⁶Represents a type group).   Synthetic routes described above for converting compounds of formula IV to compounds of formula I Does not exclude other methods described in the literature.   The starting compound of formula II is belled as Azetidon® (Japan) (3R, 4R) -4-acetoxy-3-[(R) -1- (tert-butyldimethyl) commercially available from [Silyloxy) ethyl] azetidin-2-one according to the method described in the following document Prepared:   T. Maruyama et al., Tetrahedron Lett,35, (1994) 2271; Tsuji, TetrahedronFour Two , (1986) 4401; P.J. Reider et al., Tetrahedron Lett,twenty three, (1982) 379; Yoshida et al. , Tetrahedron Lett,twenty five, (1984) 2793; Ernest et al. Am. Chem. Soc.101, (19 79) 6310; Afonso et al. Am. Chem. Soc.104, (1982) 6139; R.D. Fabio et al., Bioo rg. Med. Chem. Lett.,Five, (1995) 1235; F.A. Corey and R.J. Sundberg, Advanced Organic Chemistry Second Edition, Plenum Press, New York and London Annual Reports in Organic Synthesis 1975-1989, Academic Press Inc .; Sa Ndiego; T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons, New York p45.   The present invention will be described in more detail with reference to the following examples, which are not intended to limit the present invention. It is not specified. Made by Merck, Kieselgel 60 silica gel Column chromatography with a particle size of 0.063-0.200 in 50-100 times the amount of the charged material. Preparative chromatography manufactured by Merck, trade name Kieselgel 6 0GF₂₅₄Was performed by thin layer chromatography on a glass plate. Example 1       3,3'-diallyl thiodipropionate   Triethylamine (159.6 ml; 0.15 mol) was dissolved in allyl alcohol (945 ml) To the solution slowly add 3,3'-thiodipropionyl chloride (44.2 g; 0.2 mol) slowly Added. The resulting mixture was stirred at room temperature for another hour and then allyl alcohol The oil was evaporated on a rotary evaporator. Allyl alcohol The oily residue obtained after evaporation was treated with diethyl ether (800 ml) and 1 M hydrochloric acid (40 ml). 0 ml) was added, the resulting solution was stirred, and the organic layer and the aqueous layer were separated. The resulting water layer Was extracted with diethyl ether (400 ml × 2), and the ether layers were combined and water (200 ml) was added. × 2) and then dried using magnesium sulfate. Filter the desiccant The solvent was evaporated from the filtrate on a rotary evaporator. The obtained crude product was added in 0. Distillation at a pressure of 8 mbar gave the title compound (43.5 g; 82% yield) as a colorless oil. Obtained in the form. Its distillation temperature was 134-135 ° C.Example 2a       Allyl 4-chlorobutyrate   4-chlorobutyric acid (48 ml; 0.48 mol), allyl alcohol (200 ml) and hexane (1.2 l) Was added to p-toluenesulfonic acid (16.0 g; 0.08 mol). The resulting blend The compound is refluxed at the reflux temperature in such a way that water is simultaneously removed using a Dean-Stark device. Heated for 5 hours (Vogel's Textbook of Practical Organic Chemistry, 4th edition, L ongman, London, 1978, p.411). The resulting mixture was then cooled to room temperature, The mixture was shaken with an aqueous sodium hydrogen carbonate solution (500 ml × 2 times). The resulting solution is After drying with magnesium acid and filtering off the drying agent, the hexane was evaporated. The crude residue obtained is distilled at a temperature of 95 ° C. under a reduced pressure of 10 mbar to give the title compound (61.2 g; 79% yield) in the form of a colorless oil. Example 2b       Allyl 3-chloropropionate   The operation was carried out in the same manner as described in Example 2a. 3-chloropropionic acid (10 8.5 g; 1.0 mol), and the other reactants were in the same molar ratio as described in Example 2a. Used in. The title compound (121.8 g; yield 82%) was distilled at a pressure of 15 mbar Obtained in the form of a colorless oil at 88-91 ° C.Example 3       Allyl 4- (ethoxycarbonylmethylthio) butyrate   Sodium (9.06 g; 0.39 mol) was dissolved in allyl alcohol (380 ml). Obtained The solution was added first to ethyl mercaptoacetate (42.7 ml; 0.39 mol) at 0 ° C. In drops, then 4-chlorobutyrate ant prepared according to the method described in Example 2a. (58.3 g; 0.36 mol) was added dropwise. The resulting mixture is allowed to stand at room temperature Stir for 3 hours and then at reflux for 1 hour. The obtained reaction mixture is Concentrate by evaporation, diethyl ether (200 ml) and ice / water mixture (100 g) To the mixture. The resulting solution is diluted with 1M salt until its pH value is between 3 and 6. Acidified with acid solution. The ether layer was separated, and the resulting aqueous layer was treated with diethyl ether (2 00 ml). Combine the ether extracts and add water (200 ml) and 4% sodium bicarbonate It was washed with an aqueous solution of lithium (200 ml) and then dried using magnesium sulfate. Dry After filtering the drying agent and evaporating the ether from the filtrate, the title compound (78.1 g; yield 8 4%). It was used in crude form for the next reaction. Example 4       Ethyl [2- (allyloxycarbonyl) ethyl] thioacetate and [2- (allyloxycarbonyl) ethyl       Mixture with allyl [carbonyl] ethyl] thioacetate   Sodium (19.7 g; 0.86 mol) was dissolved in allyl alcohol (850 ml). Obtained The solution was added first to ethyl mercaptoacetate (106.2 ml; 0.86 mol) at a temperature of 0 ° C. 3-chloropropion prepared according to the method described in Example 2b Allyl acid (119.3 g; 0.81 mol) was treated dropwise. The resulting mixture Stir at room temperature for 2 hours, then at reflux temperature for 2 hours. After the reaction is completed, Allyl alcohol is evaporated from the reaction mixture, and the residue obtained after evaporation is treated with diethyl ether. Ether (400 ml) and water (200 ml) were added. The ether layer and the aqueous layer were separated, and the resulting water The layer was re-extracted with diethyl ether (200ml). 5% combined ether extracts After washing with an aqueous sodium carbonate solution (200 ml), the ether layer and the aqueous layer were separated again. Profit The diethyl ether is evaporated from the organic layer obtained and the residue is separated at a pressure of 4 mbar. Vacuum distilled. The product (158.5 g; 84% yield) is obtained as a fraction at a distillation temperature of 155-158 ° C. In the form of a colorless oil, the ethyl ester and allyl ester of the title compound Obtained as a 7: 3 mixture. This mixture is separated for further use in the reaction I didn't have to. Example 5a       Allyl 4-hydroxy-5,6-dihydro-2H-thiopyran-3-carboxylate   Granular sodium (23 g; 1.0 mol) (Vogel's Textbook of Practical Organic Chemi stry, 4th edition, Longman, London, 1978, p. 411) and anhydrous diethyl ether (3.4 l) ) Was slowly added to the mixture with (3). The resulting reaction mixture The product was stirred at room temperature for 2 days and then prepared according to the method described in Example 1, 3,3'- Diallyl thiodipropionate (129.0 g; 0.5 mol) was added slowly in small portions. Profit The resulting mixture was stirred at room temperature for a further day and then first under anhydrous ice cooling under anhydrous ethanol. (10 ml), then water (400 ml) and concentrated hydrochloric acid (455 ml), and stir until the whole is dissolved. Stirred. The organic and aqueous layers were separated. The obtained organic layer was washed with water (400 ml), With 3% aqueous sodium hydrogen carbonate solution (400 ml x 3), then again with water (200 ml) Was cleaned. The obtained organic layer is dried using magnesium sulfate, and the drying agent is filtered. The filtrate was evaporated to dryness. The title compound (42.4 g; yield 42%) was obtained as a crude product in yellow. Obtained in the form of a colored oil. Example 5b       Allyl 3-hydroxy-5,6-dihydro-4H-thiopyran-2-carboxylate   The operation was carried out in the same manner as described in Example 5a. According to the method described in Example 3. Thus prepared allyl 4- (ethoxycarbonylmethylthio) butyrate (73.8 g; 0.29 mol) And the other reactants were used in the same molar ratio as described in Example 5a. The title compound (26.1 g; 46% yield) was obtained in the form of a yellow oil. The obtained crude product The title compound of the form was used in a further reaction. Example 5c       Allyl 3-hydroxy-4,5-dihydrothiophene-2-carboxylate   The operation was carried out in the same manner as described in Example 5a. According to the method described in Example 4. Therefore, prepared ethyl [2- (allyloxycarbonyl) ethyl] thioacetate and [2- (allyloxycarbonyl) ethyl] Loxycarbonyl) ethyl] mixture with allyl thioacetate (79.0 g) The reactants were used in the same molar ratio as described in Example 5a. The indicated compound (47.5 g ; 46%) in the form of a yellow oil. This compound was used in the following procedure. There was no need for purification. Example 6a       (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(3R       S) -allyloxycarbonyl-4-oxotetrahydro-4H-thiopyran-3-i       Ru] azetidin-2-one   60% sodium hydride (3.84 g; 0.096 mol) and anhydrous tetrahydrofuran (125 ml) To the mixture of 4-hydroxy-5,6-diphenyl prepared according to the method described in Example 5a. Allyl dro-2H-thiopyran-3-carboxylate (19.22 g; 0.096 mol) The solution dissolved in rofuran (80 ml) was added little by little under ice cooling over 10 minutes. Got The mixture was stirred at room temperature for 1 hour and then with vigorous shaking (3R, 4R) -4-acetoxy. C-3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} azetidin-2-one I got it. The resulting mixture was stirred at room temperature for another hour. Add diethyl ether to this mixture. (400 ml) and water (400 ml) are added, and the resulting mixture is brought to pH 3-6. And acidified with concentrated hydrochloric acid. The organic layer and the aqueous layer were separated, and the resulting aqueous layer was distilled off. Extracted with tel (200 ml x 2). The ether extracts were then combined and combined with 7% It was washed with an aqueous sodium hydrogen solution (200 ml) and dried using magnesium sulfate. The drying agent was filtered and the filtrate was evaporated from ether. The obtained crude product is Chromatography [Carrier: silica gel; eluent: diethyl ether / petroleum ether 1: 1 (volume ratio)] to give a diastereomer mixture (15. 91 g; yield 39%). The two isomers are separated by column chromatography Can be separated and isolated, but need not be separated for use in further reactions Was. The mixture of the two diastereomers was used for further reactions. First fraction in chromatographic separation:   The diastereomer obtained was in the form of a viscous oil. Second fraction in chromatographic separation:     The resulting diastereomer has a melting point of 117-119 ° C (recrystallized from cyclohexane).   It was in the form of white crystals. Example 6b       (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(2R       S) -Allyloxycarbonyl-3-oxotetrahydrothiopyran-2-yl] a       Zetidin-2-one   Until the title compound is isolated in the form of a crude product, the procedure described in Example 6a is followed. The operation was performed as follows. 3-Hydro prepared according to the method described in Example 5b Allyl xy-5,6-dihydro-4H-thiopyran-2-carboxylate (24.4 g; 1.22 mol) The other reactants were used in the same molar ratios as described in Example 6a. Next The resulting crude product is subjected to column chromatography [carrier: silica gel; eluent : Diethyl ether / petroleum ether 2: 1 (volume ratio), diethyl ether And diastereomeric mixtures of the indicated compounds. (32.1 g; yield 62%) was obtained. A mixture of two diastereomers is a further anti- Used accordingly. First fraction in chromatographic separation:     The resulting diastereomer has a melting point of 87-91 ° C (recrystallized from cyclohexane).   It was in the form of white crystals. Second fraction in chromatographic separation:     The resulting diastereomer is white with a melting point of 109-113 ° C (recrystallized from hexane).   It was in the form of crystals. Example 6c       (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(2R       S) -Allyloxycarbonyl-3-oxotetrahydrothien-2-yl] azeti       Gin-2-one   Until the title compound is isolated in the form of a crude product, the procedure described in Example 6a is followed. The operation was performed as follows. 3-Hydro prepared according to the method described in Example 5c Using allyl xy-4,5-dihydrothiophene-2-carboxylate (40.0 g; 0.21 mol), The other reactants were used in the same molar ratio as described in Example 6a. Then The obtained crude product is subjected to column chromatography [carrier: silica gel; Etch L: 1 petroleum ether / petroleum ether (volume ratio)]. An astereomeric mixture (36.1 g; 41% yield) was obtained. These two diastereomers Was used for further reactions. First fraction in chromatographic separation:     The resulting diastereomer is a white solid with a melting point of 114-116 ° C (recrystallized from hexane).   It was in the form of crystals. Second fraction in chromatographic separation:     The resulting diastereomer was a white solid with a melting point of 79-80 ° C (recrystallized from hexane).   It was in the form of crystals.Example 7a       (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(3R       S) -4-Oxotetrahydro-4H-thiopyran-3-yl] azetidin-2-one   (3S, 4S) -3-{(R)-[1- (tert-butyldiene) prepared according to the method described in Example 6a. Methylsilyl) oxy] ethyl} -4-[(3RS) -allyloxycarbonyl-4-oxotet Lahydro-4H-thiopyran-3-yl] azetidin-2-one (15.9 g; 0.037 mol, It was dissolved in a 67 M solution of triethylammonium formate in dichloromethane (112 ml). Profit La To the solution obtained, triphenylphosphine (1.01 g; 3.9 mmol) and D.R. Coulson Dissertation, Inorganic Synthesis,13, 121 (1972). Trakis (triphenylphosphine) -palladium (O) (1.16 g; 1.0 mmol) was added. I got it. After the resulting mixture was stirred at room temperature for 1 hour, dichloromethane (170 ml) was added. The mixture was shaken with a 1M aqueous hydrochloric acid solution (80 ml). Separate the organic and aqueous layers The aqueous layer was extracted with dichloromethane (80 ml). Combine the resulting organic layers and add water (8 0 ml) and then with a 7% aqueous sodium hydrogen carbonate solution (80 ml), followed by After drying using magnesium sulfate and filtering the drying agent, the solvent is evaporated from the filtrate. I let it. The obtained crude product is subjected to column chromatography [carrier: silica gel; Effluent: ether / petroleum ether 3: 1 (volume ratio)]. The following two The diastereomers were separated and were obtained in both 75% yields. (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(3R) -4-o Oxotetrahydro-4H-thiopyran-3-yl] azetidin-2-one   The above compound (1.21 g; yield 9%) has a melting point of 148 to 15 ° C (recrystallized from hexane). Obtained in the form of colored crystals. (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(3S) -4-O Oxotetrahydro-4H-thiopyran-3-yl] azetidin-2-one   The above compound (8.48 g; yield 66%) has a melting point of 142-144 ° C (recrystallized from hexane). Obtained in the form of white crystals. Example 7b       (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(3R       S) -3-Oxotetrahydrothiopyran-2-yl] azetidin-2-one   The procedure described in Example 7a is followed until the title compound is isolated in the form of a crude product. The operation was performed in the same manner. Prepared according to the method described in Example 6b, (3S, 4S) -3-{(R )-[1- (tert-Butyldimethylsilyl) oxy] ethyl} -4-[(2RS) -allyloxycar Diastere of Bonyl-3-oxotetrahydrothiopyran-2-yl] azetidin-2-one The rheomer mixture (5.16 g; 0.012 mol) was used and the other reactants are described in Example 7a Used in the same molar ratio as. Next, the obtained crude product is subjected to column chromatography. Purification by chromatography (carrier: silica gel; eluent: diethyl ether) The following two separated diastereomers were obtained in both yields of 48%. (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(3R) -3-o Oxotetrahydrothiopyran-2-yl] azetidin-2-one   The above compound (0.61 g; yield 15%) was obtained in the form of a yellow oil. (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(3S) -3-o Oxotetrahydrothiopyran-2-yl] azetidin-2-one   The above compound (1.36 g; yield 33%) was obtained in the form of a yellow oil. Example 7c       (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(2R       S) -3-Oxotetrahydrothien-2-yl] azetidin-2-one   The procedure described in Example 7a is followed until the title compound is isolated in the form of a crude product. The operation was performed in the same manner. Prepared according to the method described in Example 6c, (3S, 4S) -3-{(R )-[1- (tert-Butyldimethylsilyl) oxy] ethyl} -4-[(2RS) -allyloxycar Diastere of Bonyl-3-oxotetrahydrothienyl-2-yl] azetidin-2-one The omer mixture (30.0 g; 0.073 mol) was used and the other reactants were as described in Example 7a. Used in the same molar ratio as the molar ratio. Next, the obtained crude product is subjected to column chromatography. Raffy [Carrier: silica gel; eluent: diethyl ether / petroleum ether 2: 1 (Volume ratio)] to give a diastereomer mixture of the title compound (6.34 g; yield 26%) in the form of white crystals with a mixture melting point of 105-108 ° C. (recrystallized from petroleum ether). Was. The two diastereomers could not be separated by this chromatography, Did not need to be separated for use in yet another reaction. The molar ratio of diastereomer A: diastereomer B = 3: 7 Example 8       (3S, 4R) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(1R       S) -2-Oxocyclohexyl] azetidin-2-one   Cyclohexanone (6.2 ml; 60 mmol) dissolved in dichloromethane (60 ml) In the solution, trimethylsilyl chloride (8.4 ml; 66 mmol) and 1,8-diazabicyclo [5.4 .0] Undec-7-ene (10.8 ml; 72 mmol) was added. The resulting mixture is warmed to 40 ° C. And stirred for 2 hours. Then, the obtained reaction solution was diluted with hexane (40 ml), It was then washed with saturated aqueous sodium bicarbonate (40 ml) and water (40 ml). Get The solution obtained is dried over sodium sulphate, then the drying agent is filtered off and the resulting filtration is carried out. The solvent was evaporated from the liquid on a rotary evaporator. The crude trimethyl obtained The silyloxycyclohexane was used for the next synthesis step without purification and Diluted with dichloromethane (15 ml) and the resulting solution was diluted with (3R, 4R) -4-acetoxy-3-[(R) -1- (ter [t-butyldimethylsilyloxy) ethyl] azetidin-2-one (8.63 g; 30 mmol) Was added to a solution dissolved in dichloromethane (10 ml). Then dichloromethane (15m l) Suspended zinc iodide (9.57 g; 30 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. did. Water (30 ml) and sodium hydrogen carbonate (2.55 g; 30 mmol) were added to the resulting reaction mixture. ) And stirred for 5 minutes. The organic layer and the aqueous layer were separated, and the aqueous layer was diluted with dichloromethane (10 ml × 2). The organic layers obtained are combined and dried over sodium sulfate. Drying then filtering the drying agent and evaporating the solvent from the filtrate gave an oily residue. Profit The obtained crude product (yield 65%) is further subjected to column chromatography [carrier: silica gel]. Eluent: dichloromethane / ethyl acetate 5: 1 (by volume)]. The two diastereomers described above were obtained. (3S, 4R) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(1R) -2-o Xoxocyclohexyl] azetidin-2-one   The above compound (2.94 g; yield 30%) is a white crystal having a melting point of 108 to 110 ° C (from ethyl acetate). Recrystallized). (3S, 4R) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(IS) -2-o Xoxocyclohexyl] azetidin-2-one   The above compound (3.44 g; yield 35%) was obtained as white crystals (melting from ethyl acetate) with a melting point of 99-101 ° C. Recrystallized). Example 9a       (8S, 9R, 10S) -10-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -1       1-oxo-1-azatricyclo [7.2.0.0^3,8] Undec-2-ene-2-carboxylic acid       Allyl   (3S, 4R) -3-{(R)-[1- (tert-butyldimethyl) prepared according to the method described in Example 8. Tylsilyl) oxy] ethyl} -4-[(1R) -2-oxocyclohexyl] azetidine-2-o Triethyl (0.8 g; 2.46 mmol) in dichloromethane (25 ml). Amine (0.99 ml; 0.72 g; 7.07 mmol) was added and the resulting mixture was cooled on an ice bath did. Allyl oxalyl chloride (0.56 ml; 0.77 g; 5.23 Was added in portions over 2 minutes and stirred at 0 ° C. for a further 15 minutes. Next Then, the obtained reaction solution is shaken with a 5% hydrochloric acid aqueous solution (30 ml), and the mixture is shaken with 5% sodium hydrogen carbonate. Shake with aqueous lithium solution (30 ml) and then with water (30 ml). Got The solution is dried with sodium sulfate, then the desiccant is filtered and the filtrate is freed from the solvent. Evaporated. Crude (3S, 4R) -2-oxo-3-{(R)-[1- (tert-butyldimethylsilylthio) [Xy) ethyl] -4-[(1R) -2-oxocyclohexyl] azetidin-1-yl} glyoxy Allyl luate [1.03 g (95% yield)] was obtained as a yellow oil.   The obtained crude intermediate, that is, the above compound (1.03 g; 2.35 mmol) was treated with toluene ( 40 ml), add hydroquinone (25 g), and heat the resulting solution at a temperature of 90 ° C. did. To this solution, with vigorous stirring, triethyl phosphite (2.04 ml; 1.9 5 g; 11.75 mmol) in portions over 5 minutes and at the same temperature (90 ° C.) Stir for 2 hours. The reaction mixture was then heated at a temperature of 120 ° C. for 10 hours. Then The solvent is evaporated from the reaction mixture obtained and the oily residue obtained is purified by column chromatography. Chromatography [carrier: silica gel; eluent: toluene / diethyl ether 4: 1] (Volume ratio)]. The title compound (578 mg; yield 61%) was a viscous yellow oil In the form of Example 9b       (8R, 9R, 10S) -10-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -1       1-oxo-1-azatricyclo [7.2.0.0^3,8] Undec-2-ene-2-carboxylic acid       Allyl   The operation was carried out in the same manner as described in Example 9a. According to the method described in Example 8 (3S, 4R) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl thus prepared } -4-[(1S) -2-oxocyclohexyl] azetidin-2-one (1.5 g; 4.62 mmol) And the other reactants were used in the same molar ratio as described in Example 9a. The title compound (1.09 g; yield 64%) was obtained in the form of a yellow oil. Example 10a       (8S, 9S, 10S) -10-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -1       1-oxo-1-aza-6-thiatricyclo [7.2.0.0^3,8] Undeca-2-ene-2-can       Allyl borate   (3S, 4S) -3-{(R)-[1- (tert-butyldiene) prepared according to the method described in Example 7a. Methylsilyl) oxy] ethyl} -4-[(3R) -4-oxotetrahydro-4H-thiopyran-3 -Yl] azetidin-2-one (1.50 g; 4.37 mmol) in anhydrous dichloromethane (20 ml) Dissolved. The resulting solution is cooled to a temperature of -20 ° C and chloroglyoxylic acid Allyl (1.95 g; 13.1 mmol) was added. Then, to the resulting mixture, Dissolve isopropylamine (3.38 g; 26.2 mmol) in anhydrous dichloromethane (5 ml) The resulting solution was added in portions over 15 minutes with stirring at a temperature of -20 <0> C. Profit The resulting mixture is stirred at the same temperature for a further 30 minutes and then at a temperature of 0 ° C. for 1 hour did. The mixture obtained is again cooled to a temperature of -20 ° C and then chloroglyoxyl A solution of allyl acid (1.95 g) dissolved in anhydrous dichloromethane (5 ml) was added for 15 minutes. And added little by little. The resulting solution is stirred for 1 hour at a temperature of 0 ° C. and then at room temperature. The mixture was further stirred for 1 hour. The resulting mixture was quickly washed with 1 M aqueous hydrochloric acid (20 ml), The aqueous layer was re-extracted with dichloromethane (20 ml) and the combined organic layers were combined with 7% sodium bicarbonate. Washed with an aqueous solution of lithium. The obtained solution is dried using magnesium sulfate, The drying agent was filtered and then the solvent was evaporated from the filtrate to give a residue. This is crude (3 (S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -4-[(3R) -4-oxo Sotetrahydrothiopyran-3-yl] azetidin-2-one-1-allyl glyoxylate Met.   The residue obtained after evaporation of the solvent was dissolved in anhydrous toluene (250 ml), Hydroquinone (60 mg; 0.5 mmol) was added to the resulting solution. The resulting mixture is The solution was heated to reflux in a hydrogen atmosphere and then triethylphosphite was added to the resulting solution. (3.62 g; 21.8 mmol) in anhydrous toluene (20 ml) was slowly added. The mixture was heated at reflux temperature in a nitrogen atmosphere for another 6 hours. The resulting reaction mixture The solvent is evaporated from the residue using a rotary evaporator, and the residue is subjected to column chromatography. Raffy [Carrier: silica gel; eluent: diethyl ether / petroleum ether 1: 5 (Volume ratio)]. The title compound (170 mg; yield 9%) was obtained in the form of an oil. Was done. Example 10b       (8R, 9S, 10S) -10-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -1       1-oxo-1-aza-6-thiatricyclo [7.2.0.0^3,8] Undeca-2-en-2-cal       Allyl borate   The operation was carried out in the same way as described in Example 10a. One described in Example 7a (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] Tyl} -4-[(3S) -4-oxotetrahydro-4H-thiopyran-3-yl] azetidin-2-o (1.5 g; 4.37 mmol), and the other reactants were in the molar ratio described in Example 10a. same The same molar ratio was used. The title compound (250 mg; yield 13.5%) was obtained in the form of an oil. Was. Example 10c       (8R, 9S, 10S) -10-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -1       1-oxo-1-aza-7-thiatricyclo [7.2.0.0^3,8] Undeca-2-en-2-cal       Allyl borate   The operation was carried out in the same way as described in Example 10a. One described in Example 7b (3S, 4S) -3-{(R)-[1- (tert-butyldimethylsilyl) oxy] Tyl} -4-[(3S) -3-oxotetrahydrothiopyran-2-yl] azetidin-2-one (1. 5g; 4.37 mmol) and the other reactants were the same molar ratio as described in Example 10a. Used at the same ratio. The title compound (125 mg; yield 6%) was obtained in the form of a yellow oil. .Example 10d       (7S, 8S, 9S) -9-{(R)-[1- (tert-butyldimethylsilyl) oxy] ethyl} -10-       Oxo-1-aza-6-thiatricyclo [6.2.0.0^3,8] Deca-2-ene-2-carboxylic acid       Allyl   The procedure was as described in Example 10a until isolation of the title compound. . (3S, 4S) -3-{(R)-[1- (tert-butyldiethyl) obtained according to the method described in Example 7c. Methylsilyl) oxy] ethyl} -4-[(2RS) -3-oxotetrahydrothien-2-yl] A diastereomeric mixture of azetidin-2-one (4.0 g; 12.1 mmol) was used. The other reactants were used in the same molar ratios as described in Example 10a. Notation compound The product is subjected to column chromatography using silica gel [eluent: diethyl ether 1: 1 petroleum ether (volume ratio)]. The title compound (0.81 g; yield) 16%) in the form of white crystals, mp 89-94 ° C. (recrystallized from hexane). Example 11a       (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8]       Allyl undeca-2-ene-2-carboxylate  (8S, 9R, 10S) -10-{(R)-[1- (tert-butyl) prepared according to the method described in Example 9a. Dimethylsilyl) oxy] ethyl} -11-oxo-1-azatricyclo [7.2.0.0^3,8] C Allyl Ndeca-2-ene-2-carboxylate (405 mg; 1 mmol) was added to tetrahydrofuran ( 10M) was added to 1M tetrabutylamine dissolved in tetrahydrofuran. Monium fluoride solution (3 ml; 3 mmol) and acetic acid (0.23 ml; 4 mmol) In addition Was. The resulting mixture was stirred at room temperature for 2 hours. Then, the obtained reaction solution was Shake with saturated aqueous sodium hydrogen solution (10 ml) and elute the resulting mixture with ethyl acetate (1 ml). 5 ml × 3 times). The combined organic layers are dried over sodium sulfate and dried. The drying agent was filtered and the solvent was evaporated from the filtrate. (8S, 9R, 10S) -10-[(R) -1-Hydro Roxyethyl] -11-oxo-1-azatricyclo [7.2.0.O^3,8] Undeca-2-en-2-ca Allyl rubonate (267 mg; 92% yield) was obtained as a yellow viscous oil.   (8S, 9R, 10S) -10-[(R) -1-hydroxyethyl] -11- obtained according to the method described above. Oxo-1-azatricyclo [7.2.0.0^3,8] Allyl undec-2-ene-2-carboxylate (26 (7 mg; 0.92 mmol) was dissolved in dichloromethane (18 ml). Place the resulting solution on an ice bath And triphenylphosphine (239 mg; 0.92 mmol) and azodical Diethyl borate (0.14 ml; 0.92 mmol) was added. Heat the resulting solution to room temperature And stirred for 15 minutes, then cooled the solution again on an ice bath and added triphenyl Phosphine (239 mg; 0.92 mmol) and diethyl azodicarboxylate (0.14 ml; 0.92 mmol) Lmol) was added. The resulting solution is again stirred at room temperature for 15 minutes, then the solvent is evaporated. And the resulting product was subjected to column chromatography (eluent: petroleum ether / Purified by ethyl acetate 2: 1). The title compound (180 mg; yield 72%) was pale yellow Obtained in the form of an oil. Example 11b       (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8]       Allyl undeca-2-ene-2-carboxylate   The operation was carried out as described in the first part of Example 11a. As described in Example 10b (8R, 9S, 10S) -10-{(R)-[1- (tert-butyldimethylsilyl) [Xy] ethyl} -11-oxo-1-aza-6-thiatricyclo [7.2.0.0^3,8] Undeca-2-E Allyl 2-carboxylate (643 mg; 1.6 mmol) was used, and the other reactants were used in Example 1. It was used in the same molar ratio as described in 1a. Crude (8R, 9R, 10S) -10-[(R) -1-hydro [Xyethyl] -11-oxo-1-azatricyclo [7.2.0.0^3,8] Undeca-2-en-2-cal Allyl borate (446 mg; 96.5% yield) was obtained in the form of a yellow oil.   The operation was continued as described in the second part of Example 11a. Crude (8R, 9R, 10S) -1 0-[(R) -1-hydroxyethyl] -11-oxo-1-azatricyclo [7.2.0.0^3,8] Unde Allyl ca-2-ene-2-carboxylate (446 mg; 1.53 mmol) was used. The crude obtained The product is subjected to column chromatography [carrier: silica gel; eluent: petroleum ether / Ethyl acetate 2: 1 (volume ratio)] to give the title compound (333 mg; yield 76%). ) Was obtained in the form of a pale yellow oil. Example 11c       (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.       0.0^3,8] Allyl undec-2-ene-2-carboxylate  Until isolation, the procedure was the same as described in Example 11a. In Example 10a (8S, 9S, 10S) -10-{(R)-[1- (tert-butyldimethylsilyl) prepared according to the method described above. L) oxy] ethyl} -11-oxo-1-aza-6-thiatricyclo [7.2.0.0^3,8] Undeca- Using allyl 2-ene-2-carboxylate (424 mg), other reactants are described in Example 11a Used in the same molar ratio as. Column chromatography of the resulting crude product -[Carrier: silica gel; eluent: diethyl ether / petroleum ether 2: 1 (volume Ratio)] to give the title compound (85 mg; 29% yield) in the form of a viscous oil. . Example 11d       (4S, 8S, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-aza-6-tri       Cyclo [7.2.0.0^3,8] Allyl undec-2-ene-2-carboxylate   The operation was carried out in the same way as described in the first part of Example 11a. Reference [C. Gh iron et al., Tetrahedron Lett.,37, (1996) 3891]. (4S, 8S, 9R, 10S) -4-methoxy-10-{(R)-[1- (tert-butyldimethylsilyl) [Xy] ethyl} -11-oxo-1-azatricyclo [7.2.0.0^3,8] Undeca-2-en-2-ca Allyl rubonate (110 mg; 0.252 mmol) was used and the other reactants were as in Example 11a. It was used in the same molar ratio as described. The obtained crude product is subjected to column chromatography. Fee [carrier: silica gel; eluent: diethyl ether / petroleum ether 1: 3 ( (Volume ratio)] to give the title compound (40 mg; yield 52%) in the form of a viscous oil. Obtained. Example 11e       (4R, 8R, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-aza-6-tri       Cyclo [7.2.0.0^3,8] Allyl undec-2-ene-2-carboxylate   The operation was carried out in the same way as described in the first part of Example 11a. Reference [C. Gh iron et al., Tetrahedron Lett.,37, (1996) 3891]. (4R, 8R, 9R, 10S) -4-methoxy-10-{(R)-[1- (tert-butyldimethylsilyl) [Xy] ethyl} -11-oxo-1-azatricyclo [7.2.0.0^3,8] Undeca-2-en-2-ca Allyl rubonate (280 mg; 0.643 mmol) was used and the other reactants were as in Example 11a. It was used in the same molar ratio as described. The obtained crude product is subjected to column chromatography. Fee [carrier: silica gel; eluent: diethyl ether / petroleum ether 1: 3 ( (Volume ratio)] to give the title compound (120 mg; yield 64%) in the form of a viscous oil. Obtained. Example 12       (8R, 9S, 10S) -10-[(R) -1- (methanesulfonyloxy) ethyl] -11-oxo-1-       Aza-6-thiatricyclo [7.2.0.0^3,8] Undec-2-ene-2-carboxylic acid ant       Le   (8R, 9S, 10S) -10-{(R)-[1- (tert-butyl) obtained according to the method described in Example 10b. Dimethylsilyl) oxy] ethyl} -11-oxo-1-aza-6-thiatricyclo [7.2.0. 0^3,8] Undeca-2-ene-2-carboxylate allyl (652 mg; 1.54 mmol) in anhydrous tetra Dissolved in hydrofuran (8 ml). In the resulting solution, dissolve in tetrahydrofuran 1M tetrabutylammonium fluoride solution (4.62 ml; 4.62 mmol) and vinegar Acid (0.37 g; 6.2 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours. Then, ethyl acetate (36 ml) and water (18 ml) were added to the reaction mixture. Organic and aqueous layers And the aqueous layer was re-extracted with ethyl acetate (18 ml). Combine the resulting organic layers And washed with 7% aqueous sodium hydrogen carbonate solution and dried using magnesium sulfate . The drying agent was then filtered and the solvent was evaporated from the filtrate. Residue after evaporation of the solvent The distillate was dissolved in anhydrous dichloromethane (40 ml) and the resulting solution was first triturated at 0 ° C. Cylamine (615 mg; 6.1 mmol) was added, followed by methanesulfonyl chloride (353 mg; 3.1 mmol). The resulting mixture was stirred on ice bath for another 30 minutes. Solvent is evaporated with a rotary evaporator, and the residue after evaporation of the solvent is dissolved at high speed. Ram chromatography [Carrier: silica gel; eluent: diethyl ether / petroleum Ether 3: 1 (volume ratio)]. The title compound (130 mg; 22% yield) Obtained in the form of a viscous oil. Example 13       (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.       0.0^3,8] Allyl undec-2-ene-2-carboxylate   (8R, 9S, 10S) -10-[(R) -1- (methanesulfur) obtained according to the method described in Example 12. Honyloxy) ethyl] -11-oxo-1-aza-6-thiatricyclo [7.2.0.0^3,8] Unde Allyl ca-2-ene-2-carboxylate (55 mg; 0.14 mmol) was added to anhydrous dichloromethane (20 ml). The resulting mixture was cooled to a temperature of -20 ° C and 1,8-diazabicyclo [ 5.4.0] Undec-7-ene (21.4 mg; 0.14 mmol) was added. The resulting solution is -20 At -20 ° C to 0 ° C for 2 hours. Stirred at room temperature for 1 hour. The solvent is then removed from the reaction solution by evaporation in vacuo, The obtained isolated product is subjected to column chromatography [carrier: silica gel; eluent: Diethyl ether / petroleum ether 3: 1 (volume ratio)]. Notation compound (30 mg; 72% yield) in the form of a viscous oil. Example 14       (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.       0.0^3,8] Allyl undec-2-ene-2-carboxylate   The operation was carried out in the same manner as described in Example 12. The one described in Example 10b (8R, 9S, 10S) -10-{(R)-[1- (tert-butyldimethylsilyl) oxy) [Shi] ethyl} -11-oxo-1-aza-6-thiatricyclo [7.2.0.0^3,8] Undeca-2-ene- Allyl 2-carboxylate (650 mg; 1.53 mmol) was used, and the other reactants were used in Example 12. Used in the same molar ratio as described in the above. The obtained crude product is treated with diethyl ether / Petroleum ether was eluted through a silica gel column using a 3: 1 mixture. Methanesulfonic acid was spontaneously eliminated and the title compound was isolated. The indicated compound (1 52 mg; 34% yield). This is a compound prepared by the method described in Example 13. It was the same compound as the product. Example 15a       (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8]       Sodium undeca-2-ene-2-carboxylate   (8S, 9R) -10-[(E) -ethylidene] -11-o prepared according to the method described in Example 11a. Oxo-1-azatricyclo [7.2.0.0^3,8] Allyl undeca-2-ene-2-carboxylate (73mg 0.267 mmol) in tetrahydrofuran / dichloromethane at a volume ratio of 1: 1. Dissolved in the mixture (0.5 ml). The resulting solution is first charged with triphenylphosphine (24 mg; 0.08 mmol) and then sodium 2-ethylhexanoate (46.8 mg; 0.28 mmol) Mol) and tetrakis (triphenylphosphine) -palladium (O) (32 mg; 0.024 mm Mol) [D.R. Coulson's paper, Inorganic Synthesis, 13, 121 (1972) Prepared according to the method described above) and tetrahydrofuran / dichloromethane (1: 1) Solution (2 ml) was added. The resulting mixture was stirred at room temperature for 30 minutes. Profit Diethyl ether (4 ml) was added to the resulting mixture and cooled to 0 ° C. Separate generation The product is filtered and washed with an anhydrous mixture of diethyl ether / tetrahydrofuran And then vacuum dried. The title compound (32 mg; 47% yield) has a melting point of 222-225 ° C. (Decomposed) in the form of brown crystals (recrystallized from DMF-diethyl ether). Example 15b       (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8]       Sodium undeca-2-ene-2-carboxylate   The operation was carried out in the same manner as described in Example 15a. According to the method described in Example 11b Thus prepared (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2 .0.0^3,8Using allyl undeca-2-ene-2-carboxylate (100 mg; 0.37 mmol) The other reactants were used in the same molar ratios as described in Example 15a. Crude product (48 mg; Yield: 51%). Melting point: 215-219 ° C (decomposition). (Crystal). Example 15c       (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.       0.0^3,8] Sodium undeca-2-ene-2-carboxylate   The operation was carried out in the same manner as described in Example 15a. In accordance with the method described in Example 11c The resulting (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatrici Black [7.2.0.0^3,8] Allyl undec-2-ene-2-carboxylate (100mg; 0.35mmol) And the other reactants were used in the same molar ratio as described in Example 15a. The crude product (78 mg; yield 83%) was obtained as brown crystals (DMF-ether Recrystallized). Example 15d       (8R, 9R) -10-[(E) -Ethylidene] -11-oxo-1-aza-6-thiatricyclo       [7.2.0.0^3,8] Sodium undeca-2-ene-2-carboxylate   The operation was carried out in the same manner as described in Example 15a. According to the method described in Example 14. The resulting (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatrici Black [7.2.0.0^3,8] Allyl undec-2-ene-2-carboxylate (100mg; 0.35mmol) And the other reactants were used in the same molar ratio as described in Example 15a. The crude product (38 mg; yield 40%) was white crystals (DMF-ether Recrystallized). Example 15e       (4S, 8S, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatrisic       B [7.2.0.0^3,8] Sodium undeca-2-ene-2-carboxylate   The operation was carried out in the same manner as described in Example 15a. Following the method described in Example 11d The resulting (4S, 8S, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-aza -6-tricyclo [7.2.0.0^3,8] Allyl undeca-2-ene-2-carboxylate (33 mg; 0.109 Mmol), and the other reactants were used in the same molar ratio as described in Example 15a. Used. The crude product (13 mg; yield 43%) was obtained as white crystals (DMF-d (Recrystallized from water). Example 15f       (4R, 8R, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatrisic       B [7.2.0.0^3,8] Sodium undeca-2-ene-2-carboxylate   The operation was carried out in the same manner as described in Example 15a. Following the method described in Example 11e (4R, 8R, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-aza thus prepared -6-tricyclo [7.2.0.0^3,8] Allyl undeca-2-ene-2-carboxylate (70 mg; 0.231 Mmol), and the other reactants were used in the same molar ratio as described in Example 15a. Used. The crude product (46 mg; 69% yield) was obtained as white crystals (DMF-d (Recrystallized from water).

[Procedure for Amendment] Article 184-8, Paragraph 1 of the Patent Act [Date of Submission] November 24, 1998 (1998.11.24) [Content of Amendment] US5372993, US5374630, PCT-WO-94 / 21637 No., PCT-WO-94 / 21638, PCT-WO-9 5/03700, PCT-WO-95 / 13278, PCT-WO-95 / 23149, JP06,166688 and JP08,53459 Are also disclosed. Compound 4S, 8S-4-methoxy- (9R, 10R, 12R) -10- (1-hydroxyethyl) -11-oxo-1-azatricyclo- [7.2.0.0 ^3,8 ] undec-2-ene (GV104326 , Sanfetrinem] are biologically active substances which have an action on the enzyme D, D-peptidase which is essential for the bacterial growth process [E. diModugno et al., Anti microb. Agents Chemother., 38 (1994), 2362]. Bicyclic carbapenem compounds with antibacterial activity are described in EP-A-005349 and US Pat. No. 4,235,922. No data exists for the compounds described above, which are inhibitors of the enzyme β-lactamase. For all of the previously disclosed tricyclic carbapenem compounds, there is no data on the inhibitory effect of β-lactamase species on enzymes. Accordingly, an object of the present invention is to provide a novel ethylidene derivative of a tricyclic carbapenem compound having a completely novel structure and having the property of inhibiting the enzyme β-lactamase. This property does not diminish its important antimicrobial activity. Technical Solution The present invention provides a compound of formula I: Wherein the ring labeled C fused to the basic carbapenem nucleus at the 3- and 4-positions is a 5, 6 or 7 membered ring, wherein: One or more carbon atoms in the ring labeled C may be mono- or di-substituted with the following substituents, which may be the same or different: a) a hydrogen atom, b) 1-20 Saturated alkyl chain having three carbon atoms; the saturated alkyl chain is straight-chain (eg, methyl, ethyl, n-propyl, n-butyl) or branched at any position (eg, isopropyl, s- Butyl, isobutyl, isoamyl, tert- Claims 1. Formula I: Wherein the ring labeled C fused to the basic carbapenem nucleus at the 3- and 4-positions is a 5, 6 or 7 membered ring, wherein: i. One or more carbon atoms of may be mono- or di-substituted with the following substituents, which may be the same or different: a) hydrogen atom, b) saturated having 1 to 20 carbon atoms Alkyl chain; the saturated alkyl chain may be straight-chain or branched at any position, and each of the members of the chain is halo, hydroxy, (C ₁ -C ₄ ) alkyloxy, mercapto And (C ₁ -C ₄ ) alkyl mercapto, (C ₁ -C ₄ ) alkanesulfonyl, amino, (C ₁ -C ₄ ) alkylamino and di- (C ₁ -C ₄ ) alkylamino, alkyleneamino, guadinino, unsubstituted N ¹ - mono-, N ³ - mono, N ^1, N ³ - di and N ^3, N ³ - di - (C ₁ -C ₄₎ formamidino, Aromatic ring or thienyl, furyl or pyridyl ring, (C ₁ -C ₄₎ alkyloxycarbonyl, cyano, by such substituent oxo be mono- or di-substituted; c) unsaturated having 1 to 20 carbon atoms Alkyl chain; this unsaturated alkyl chain can be straight-chain and have a double or triple bond or branched at any position and have a double or triple bond. And each of the members of the chain is halo, hydroxy, (C ₁ -C ₄ ) alkyloxy, thio and (C ₁ -C ₄ ) alkylthio, (C ₁ -C ₄ ) alkanesulfonyl, amino, (C ₁ -C ₄ ) alkylamino and di- (C ₁ -C ₄ ) alkylamino, aromatic ring or thienyl, furyl or pyridyl ring, (C ₁ -C ₄ ) alkyloxycarbonyl, cyano, oxo Or di-substituted; d) 3-7 Membered saturated or partially unsaturated cycloalkyl group; the ring can contain one or more oxygen, sulfur or nitrogen atoms, and each of the ring members is halo, hydroxy, ( C ₁ -C ₄₎ alkyloxy, thio and (C ₁ -C ₄₎ alkylthio, (C ₁ -C ₄₎ alkanesulfonyl, amino, (C ₁ -C ₄₎ alkylamino and di - (C ₁ -C ₄ ) Alkylamino, (C ₁ -C ₄ ) alkyloxycarbonyl, cyano, oxo may be mono- or di-substituted by substituents; e) aromatic rings or thienyl, furyl or pyridyl rings, f) hydroxy, (C ₁ -C ₁₀ ) alkyloxy, mono- or di-substituted- (C ₁ -C ₁₀ ) alkyloxy, acyloxy, mono-, di- or tri- (C ₁ -C ₄ ) alkylsilyloxy group, g) mercapto, (C _1- C ₁₀₎ alkylmercapto, mono or di-substituted - (C ₁ -C ₁₀₎ alkyl mercapto, A Rumerukaputo group, h) amino, (C ₁ -C ₄₎ alkylamino and di - (C ₁ -C ₄₎ alkylamino, acetylamino, allyloxycarbonylamino, iminomethylamino amino, N- methylamino methyleneamino, N , N-dimethylaminomethyleneamino, guanidino, cyanoguanidino, methyleneguanidino group, i) halo atom, j) azide, nitro, cyano, (C ₁ -C ₄ ) alkyloxycarbonyl group, k) (C ₁ -C ₄ ) -Alkanesulfonyl groups; ii. One or more carbon atoms in the ring labeled C are connected to the ring labeled C via a double bond in the form> C ^* = CR ¹ R ² , substituted or Where C ^* represents a carbon atom in the ring marked C, = represents an exocyclic double bond, and the substituents R ¹ and R ² are the same Or different and means: a) a hydrogen atom, b) an unsubstituted saturated alkyl chain having 1 to 20 carbon atoms; this unsubstituted saturated alkyl chain is straight-chain or optional C) an unsubstituted unsaturated alkyl chain having 1 to 20 carbon atoms; this unsubstituted unsaturated alkyl chain may be straight-chain or branched at any position And may have a double or triple bond; d) 3-7 membered saturated or partially unsaturated. Saturated unsubstituted cycloalkyl or heteroaryl, e) aromatic rings or thienyl, furyl or pyridyl rings, f) saturated or partially unsaturated substituted alkyl chains or substituted carboxyl rings of 3 to 7 carbons; Or any carbon atom in the ring is halo, hydroxy, (C ₁ -C ₄ ) alkyloxy, (C ₁ -C ₄ ) alkylthio, (C ₁ -C ₄ ) alkanesulfonyl, amino, (C ₁ -C ₄ ) Alkylamino, di- (C ₁ -C ₄ ) alkylamino, (C ₁ -C ₄ ) alkyloxycarbonyl, cyano, oxo may be mono- or di-substituted by substituents; g) hydroxy, (C _1- C ₄₎ alkyl, acyloxy, mercapto, (C ₁ -C ₄₎ alkylmercapto, amino, (C ₁ -C ₄₎ alkylamino, di - (C ₁ -C ₄₎ alkylamino and acylamino group, h) nitro , cyano, (C ₁ -C ₄₎ alkyloxycarbonyl group; Substituent R ¹ and R ² are closed linked alkylene chain forming a ring _{(CH 2) n (n =} 2~7) can also be represented, any methylene (-CH ₂ -) configuration gave the oxa (-O-), thia (-S-), imino (-NH-) or (C ₁ -C ₄₎ may be substituted by an alkyl amino group;. iii 1 or in the ring marked with a reference numeral C or These carbon atoms can be replaced by a heteroatom via a double bond; iv. One or more carbon atoms in the ring labeled C may be substituted with a closed ring-forming substituent to form a spiro compound; Besides being an atom, it may be an oxygen, sulfur and nitrogen atom; v. One or more carbon atoms in the ring marked C may be replaced by an oxygen atom; vi. One or more carbon atoms in the ring labeled C may be replaced by a sulfur atom which may be oxidized by one or two oxygens; vii. one or more carbon atoms,> may be substituted with a nitrogen atom which may be substituted in the form of N ^* -R ^3; in the above, N ^* represents a nitrogen atom in the ring marked with a reference numeral C, R ³ Means: a) a saturated alkyl chain having 1 to 20 carbon atoms; an unsubstituted saturated alkyl chain having 1 to 20 carbon atoms is straight-chain or branched at any position. And each of the members of the chain is halo, hydroxy, (C ₁ -C ₄ ) alkyloxy, (C ₁ -C ₄ ) alkylthio, (C ₁ -C ₄ ) alkanesulfonyl, amino , (C ₁ -C ₄ ) alkylamino, di- (C ₁ -C ₄ ) alkylamino, aromatic ring or thienyl, furyl or pyridyl ring , (C ₁ -C ₄ ) alkyloxycarbonyl, cyano, oxo, imino, which may be substituted by one or more substituents; b) an unsubstituted unsaturated alkyl chain having from 1 to 20 carbon atoms; The unsubstituted unsaturated alkyl chain can be straight-chain and have a double or triple bond or branched at any position and have a double or triple bond; c) 3- 7-membered saturated or partially unsaturated unsubstituted cycloalkyl or heteroaryl group, d) aromatic ring or thienyl, furyl or pyridyl ring, e) cyano, (C ₁ -C ₄ ) alkyloxycarbonyl, aminocarbonyl A group such as, (C ₁ -C ₄ ) alkylaminocarbonyl, (C ₁ -C ₄ ) alkanesulfonyl; X is i. A hydrogen atom; ii. An alkali metal, iii. An alkaline earth metal, iv. Ammonium ions or mono-, di- or tri-substituted, acyclic or cycloaliphatic amines in protonated form or certain other nitrogen bases in protonated form, v. Quaternary ammonium ions, vi. Group R ⁴ ; is this group a) a group selected from (C ₁ -C ₂₀ ) alkyl, (C ₁ -C ₂₀ ) alkenyl, substituted alkyl, substituted silyl and phthalidyl; b) Wherein R ⁵ represents hydrogen, lower alkyl having 1 to 4 carbon atoms, and R ⁶ represents hydrogen, alkyl, cycloalkyl, alkoxy, cycloalkoxy, cycloalkylalkyl, alkenyloxy, phenyl. An ethylidene derivative of a tricyclic carbapenem represented by the following formula: 2. Formula I: Wherein the ring with the symbol C and X have the meaning of claim 1 and in the form of pure diastereomers, the ethylidene derivative of a tricyclic carbapenem. 3. Formula I: A tricyclic carbapenem ethylidene derivative in the form of a pure geometric isomer represented by the formula: wherein the ring with the symbol C and X have the meaning according to claim 1. 4. (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic acid, pharmaceutically acceptable The ethylidene derivative of the tricyclic carbapenem according to claim 1, which is a salt or an ester. 5. (8R, 9R) -10-[(E) -Ethylidene] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic acid, pharmaceutically acceptable The ethylidene derivative of the tricyclic carbapenem according to claim 1, which is a salt or an ester. 6. (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic acid, preparations thereof 2. The ethylidene derivative of a tricyclic carbapenem according to claim 1, which is a chemically acceptable salt or ester. 7. (8R, 9R) -10-[(E) -Ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic acid, preparations thereof 2. The ethylidene derivative of a tricyclic carbapenem according to claim 1, which is a chemically acceptable salt or ester. 8. (4S, 8S, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic acid, preparations thereof 3. The ethylidene derivative of a tricyclic carbapenem according to claim 1, which is a chemically acceptable salt or ester. 9. (4R, 8R, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic acid, preparations thereof 2. The ethylidene derivative of a tricyclic carbapenem according to claim 1, which is a chemically acceptable salt or ester. Ten. (4S, 8S, 9R) -4-methoxymethyl-10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic acid, The ethylidene derivative of a tricyclic carbapenem according to claim 1, which is a pharmaceutically acceptable salt or ester. 11． (4R, 8R, 9R) -4-methoxymethyl-10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0 ^3,8 ] undec-2-en-2-carboxylic acid, The ethylidene derivative of a tricyclic carbapenem according to claim 1, which is a pharmaceutically acceptable salt or ester. 12． i. Formula II (Wherein R ⁷ represents an easily removable ester protecting group and the ring with the symbol C has the meaning of claim 1). Reaction with a reactive acid derivative or with an acid R ⁸ OH (R ⁸ has the meaning set out below) in a solvent in the presence of a base in the presence of a base gives a compound of formula III (Wherein, R ⁷ and the ring with the symbol C have the above-mentioned meanings, and R ⁸ is-an aliphatic acid derivative,-an alkanesulfonic acid derivative,-an arenesulfonic acid derivative,-a heteroarenesulfonic acid derivative. Ii. Of formula III (Wherein R ⁷ , R ⁸ and the ring with the symbol C have the above-mentioned meaning) by removing the compound in an inert organic solvent at −78 ° C. to the reflux temperature of the solvent using a base as a catalyst. , Formula IV Wherein R ⁷ and the ring labeled C have the meanings given above; iii. Formula IV (Wherein R ⁷ and the ring with the symbol C have the meanings given above) are prepared according to the customary methods for the removal of protecting groups by the formula I: Wherein the ring with the symbol C has the meaning given above; (Wherein the ring with the symbol C and X have the meanings as defined in claim 1), a process for producing an ethylidene derivative of a tricyclic carbapenem. 13. i. Formula II (Wherein R ⁷ represents an easily removable ester protecting group, and the ring with the symbol C has the meaning of claim 1). At the reflux temperature of in the presence of phosphine with a diazacarboxylate to give a compound of formula IV Wherein the ring with R ⁷ and the letter C has the meaning given above; ii. Formula IV (Wherein R ⁷ and the ring with the letter C have the meanings given above) are prepared according to the customary methods for the removal of protecting groups by the formula I Wherein the ring with the symbol C has the meaning given above; (Wherein the ring with the symbol C and X have the meanings as defined in claim 1), a process for producing an ethylidene derivative of a tricyclic carbapenem. 14. A therapeutically effective amount of an ethylidene derivative of the tricyclic carbapenem of formula I according to claim 1 in the form of an acid, a pharmaceutically acceptable salt or ester, as an active ingredient, and further comprising a conventional formulation A pharmaceutical composition comprising a chemically acceptable carrier or auxiliary substance. 15． 3. A therapeutically effective amount of an ethylidene derivative of a tricyclic carbapenem of formula I according to claim 1 in the form of an acid, a pharmaceutically acceptable salt or ester, and a therapeutically effective amount of a β-lactam antibiotic. A pharmaceutical composition comprising, as an active ingredient, and further comprising a usual pharmaceutically acceptable carrier or auxiliary substance. 16． Use of an ethylidene derivative of a tricyclic carbapenem of formula I according to claim 1 in the form of an acid, a pharmaceutically acceptable salt or ester for the prevention and treatment of bacterial infection in humans and animals. 17． 2. The enzyme β-lactamase in human and veterinary medicine of the ethylidene derivative of the tricyclic carbapenem of formula I according to claim 1 in the form of an acid, a pharmaceutically acceptable salt or ester. Use as an inhibitor. 18． An ethylidene derivative of a tricyclic carbapenem of formula I according to claim 1 in the form of an acid, a pharmaceutically acceptable salt or an ester for use in the prevention and treatment of bacterial infection in humans and animals. 19. An ethylidene derivative of a tricyclic carbapenem of formula I according to claim 1, in the form of an acid, a pharmaceutically acceptable salt or an ester, for use as an inhibitor of the enzyme β-lactamase in human and veterinary medicine.

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, M W, SD, SZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AL, AM , AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, E S, FI, GB, GE, GH, GW, HU, ID, IL , IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, M K, MN, MW, MX, NO, NZ, PL, PT, RO , RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, Y U, ZW (72) Inventor Anti Bolt Bolt             Republic of Slovenia 1234 Menges, G             Luzin, Vegova 7 (72) Inventors Kussman, Tadea             Republic of Slovenia 1000 Liubrija             Na, Krivetsk 3 (72) Inventors Mesal, Thomas             Republic of Slovenia 1234 Menges, G             Luzin, Mengeska 64 (72) Inventors Kokuyan, Dalco             Republic of Slovenia 1000 Liubrija             Na, Mallortova 3

Claims (1)

[Claims]   1. Formula I: Wherein the ring labeled C fused to the basic carbapenem nucleus at positions 3 and 4 Is 5, 6 or 7 shrine rings, in which i. One or more carbon atoms in the ring marked C may be the same or different. Can be mono- or di-substituted with the following substituents:   a) hydrogen atom,   b) a saturated alkyl chain having 1 to 20 carbon atoms; Or branched at any position, and each of the members of the chain Is halo, hydroxy, (C₁-C_Four) Alkyloxy, mercapto and (C₁-C_Four) Alkyl Mercapto, (C₁-C_Four) Alkanesulfonyl, amino, (C₁-C_Four) Alkylamino and Di- (C₁-C_Four) Alkylamino, alkyleneamino, guadinino, unsubstituted N¹-Things, N^Three -Things, N¹, N^Three-J and N^Three, N^Three-Ji- (C₁-C_Four) Formamidino, aromatic or heteroaromatic Tribe 5 or 6 ring, (C₁-C_Four) Such as alkyloxycarbonyl, cyano, and oxo May be mono- or di-substituted by substituents; c) unsaturated with 1-20 carbon atoms Unsaturated alkyl chain; this unsaturated alkyl chain is straight-chain and has a double or triple bond Having a double bond or a triple bond Each of which has a halo, hydroxy, (C₁-C_Four) Alkyloxy, thio and (C₁-C_Four) Alkylthio, (C₁-C_Four) Alkansul Honyl, amino, (C₁-C_Four) Alkylamino and di- (C₁-C_Four) Alkylamino, aromatic Aromatic or heteroaromatic 5 or 6 shoulder ring, (C₁-C_Four) Alkyloxycarbonyl, cyano , Oxo, etc. Or di-substituted;   d) a 3-7 membered saturated or partially unsaturated cycloalkyl group; Can contain one or more sulfur or nitrogen atoms, and Each of the members is halo, hydroxy, (C₁-C_Four) Alkyloxy, thio and (C₁-C_Four) Archi Lucio, (C₁-C_Four) Alkanesulfonyl, amino, (C₁-C_Four) Alkylamino and di- ( C₁-C_Four) Alkylamino, (C₁-C_Four) Alkyloxycarbonyl, cyano, oxo May be mono- or di-substituted by substituents such as;   e) aromatic or heteroaromatic 5- or 6-membered ring,   f) hydroxy, (C₁-C_Ten) Alkyloxy, mono- or disubstituted- (C₁-C_Ten) Archi Ruoxy, acyloxy, mono, di or tri- (C₁-C_Four) Alkylsilyloxy group,   g) Mercapto, (C₁-C_Ten) Alkyl mercapto, mono- or di-substituted- (C₁-C_TenA) Alkyl mercapto, acyl mercapto group,   h) amino, (C₁-C_Four) Alkylamino and di- (C₁-C_Four) Alkylamino, acetyl Ruamino, allyloxycarbonylamino, iminomethylamino, N-methylamido Nomethyleneamino, N, N-dimethylaminomethyleneamino, guanidino, cyanog Anidino, methylene guanidino group,   i) halo atom,   j) azide, nitro, cyano, (C₁-C_Four) Alkyloxycarbonyl group,   k) (C₁-C_Four) -Alkanesulfonyl group; ii. One or more carbon atoms in the ring labeled C are> C^*= CR¹R^TwoIn the form of A substituted or unsubstituted alkyl chain linked to the ring labeled C via a double bond May be substituted with^*Represents a carbon atom in the ring with the symbol C, and = is exocyclic Represents a double bond, and represents a substituent R¹And R^TwoAre the same or different and Means:   a) hydrogen atom,   b) an unsubstituted saturated alkyl chain having 1 to 20 carbon atoms; The kill chain can be straight-chain or branched at any position,   c) an unsubstituted unsaturated alkyl chain having 1 to 20 carbon atoms; The alkyl chain is straight-chain or branched at any position and is double-bonded. Or may have a triple or triple bond;   d) 3-7 membered saturated or partially unsaturated unsubstituted cycloalkyl or heteroaryl reel,   e) a 5- or 6-membered aromatic or heteroaromatic ring,   f) a saturated or partially unsaturated substituted alkyl chain or a 3-7 membered substituted carboxy Where any carbon atom in the chain or ring is halo, hydroxy, (C₁-C_FourA) Ruxyoxy, (C₁-C_Four) Alkylthio, (C₁-C_Four) Alkanesulfonyl, amino, (C₁ -C_Four) Alkylamino, di- (C₁-C_Four) Alkylamino, (C₁-C_Four) Alkyloxycal May be mono- or di-substituted by substituents such as bonyl, cyano, oxo;   g) hydroxy, (C₁-C_Four) Alkyloxy, acyloxy, mercapto, (C₁-C_Four ) Alkyl mercapto, amino, (C₁-C_Four) Alkylamino, di- (C₁-C_Four) Alkyl Amino and acylamino groups,   h) Nitro, cyano, (C₁-C_Four) Alkyloxycarbonyl groups;   Substituent R¹And R^TwoIs a linked alkylene chain that is closed to form a ring (CH_Two)_n(n = 2 ~ 7) can also be represented, and any methylene (-CH_Two ^-Constituents are oxa (-O-) and thia (- S-), imino (-NH-) or (C₁-C_Four) Can be substituted by an alkylamino group; iii. One or more carbon atoms in the ring labeled C may be May be substituted with a heteroatom; iv. One or more carbon atoms in the ring labeled C forms a spiro compound Ring-forming substituents to form a ring; and ring configuration Members can be oxygen, sulfur and nitrogen atoms in addition to being carbon atoms; v. One or more carbon atoms in the ring marked C are replaced by oxygen atoms. obtain; vi. One or more carbon atoms in the ring denoted by C are one or two oxygen atoms Can be replaced by a sulfur atom which can be oxidized with vii. One or more carbon atoms in the ring labeled C are> N^*-R^ThreeReplace with the form N can be replaced with a nitrogen atom;^*Is in the ring labeled C Represents a nitrogen atom, R^ThreeMeans the following:   a) a saturated alkyl chain having 1 to 20 carbon atoms; having 1 to 20 carbon atoms Unsubstituted saturated alkyl chains can be straight-chain or branched at any position. And each of the chain build-ups is halo, hydroxy, (C₁-C_Four) Alkyloxy , (C₁-C_Four) Alkylthio, (C₁-C_Four) Alkanesulfonyl, amino, (C₁-C_Four) Archi Ruamino, di- (C₁-C_Four) Alkylamino, 5 or 6 aromatic or heteroaromatic rings , (C₁-C_Four) Substituents such as alkyloxycarbonyl, cyano, oxo, imino May be replaced by one or more of:   b) an unsubstituted unsaturated alkyl chain having 1 to 20 carbon atoms; The alkyl chain is straight-chain and has double or triple bonds or at any position It can be branched and have double or triple bonds;   c) 3-7 membered saturated or partially unsaturated unsubstituted cycloalkyl or heteroaryl Reel base,   d) a 5- or 6-membered unsubstituted aromatic or heteroaromatic ring,   e) Cyano, (C₁-C_Four) Alkyloxycarbonyl, aminocarbonyl, (C₁-C_Four) Alkylaminocarbonyl, (C₁-C_Four) Groups such as alkanesulfonyl; X is i. Hydrogen atom, ii. Alkali metal, iii. alkaline earth metals, iv. Mono-, di- or tri-substituted, non-cyclic, ammonium ions or protonated forms A formula or cycloaliphatic amine or some other nitrogen base in protonated form; v. Quaternary ammonium ions, vi. Group R^FourThis group   a) (C₁-C₂₀) Alkyl, (C₁-C₂₀) Alkenyl, substituted alkyl, substituted silyl, Is a group selected from taridyl;   b) The following formula (Where R^FiveRepresents hydrogen, lower alkyl having 1 to 4 carbon atoms,⁶Is water Element, alkyl, cycloalkyl, alkoxy, cycloalkoxy, cycloalkyl Alkyl, alkenyloxy, and phenyl). Ethylidene derivatives of tricyclic carbapenems.   2. Formula I: (Wherein the ring with symbol C and X have the meaning of claim 1) And an ethylidene derivative of a tricyclic carbapenem in the form of a pure diastereomer.   3. Formula I: (Wherein the ring with symbol C and X have the meaning of claim 1) And an ethylidene derivative of a tricyclic carbapenem in the form of pure geometric isomers.   4. (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8 ] Undeca-2-ene-2-carboxylic acid, a pharmaceutically acceptable salt or ester thereof.   5. (8R, 9R) -10-[(E) -ethylidene] -11-oxo-1-azatricyclo [7.2.0.0^3,8] Undec-2-ene-2-carboxylic acid, a pharmaceutically acceptable salt or ester thereof.   6. (8S, 9R) -10-[(E) -ethylidene] -11-oxo-1-aza-6-thiatricyclo [7. 2.0.0^3,8] Undeca-2-ene-2-carboxylic acid, its pharmaceutically acceptable salt or d Steal.   7. (8R, 9R) -10-[(E) -Ethylidene] -11-oxo-1-aza-6-thiatricyclo [7.2.0.0^3,8] Undeca-2-ene-2-carboxylic acid, a pharmaceutically acceptable salt thereof or ester.   8. (4S, 8S, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatrici Black [7.2.0.0^3,8] Undec-2-ene-2-carboxylic acid, a pharmaceutically acceptable salt thereof Or esters.   9. (4R, 8R, 9R) -4-methoxy-10-[(E) -ethylidene] -11-oxo-1-azatrici Black [7.2.0.0^3,8] Undec-2-ene-2-carboxylic acid, a pharmaceutically acceptable salt thereof Or esters.   Ten. (4S, 8S, 9R) -4-methoxymethyl-10-[(E) -ethylidene] -11-oxo-1-aza Tricyclo [7.2.0.0^3,8] Undec-2-ene-2-carboxylic acid, its pharmaceutically acceptable properties Salt or ester.   11． (4R, 8R, 9R) -4-methoxymethyl-10-[(E) -ethylidene] -11-oxo-1-aza Tricyclo [7.2.0.0^3,8] Undec-2-ene-2-carboxylic acid, its pharmaceutically acceptable properties Salt or ester.   12． i. Formula II (Where R⁷Represents an easily removable ester protecting group, and the ring with the symbol C represents The compound having the meaning described in claim 1) is reacted with an inert organic solvent at -78 ° C to reflux temperature. Reacting with a reactive acid derivative in the presence of a base in the agent or acid R⁸OH (R⁸Is described below Having the meaning of formula III (Where R⁷And the ring with the symbol C has the above-mentioned significance,⁸Is   -Aliphatic acid derivatives,   Alkanesulfonic acid derivatives,   -Arenesulfonic acid derivatives,   -Heteroarene sulfonic acid derivatives Which can be: ii. Formula III (Where R⁷, R⁸And the ring with the symbol C has the above-mentioned meaning). In an active organic solvent, base-catalyzed removal at -78 ° C to the reflux temperature of the solvent yields the formula IV (Where R⁷And the ring with the letter C has the meaning given above). ; iii. Formula IV (Where R⁷And the ring with the symbol C has the above-mentioned significance), Following the usual methods for the removal of Wherein the ring with the letter C has the meaning given above. Characteristic, Formula I (Wherein the ring with symbol C and X have the meaning of claim 1) A method for producing an ethylidene derivative of a tricyclic carbapenem.   13. i. Formula II(Where R⁷Represents an easily removable ester protecting group, and the ring with the symbol C represents The compound having the significance described in claim 1) is treated in an inert organic solvent at -78 ° C to Reaction with diazacarboxylate at reflux temperature in the presence of phosphine gives a compound of formula IV (Where R⁷And the ring with the letter C has the meaning given above). ; ii. Formula IV (Where R⁷And the ring with the symbol C has the above-mentioned significance), Following the usual methods for the removal ofWherein the ring with the letter C has the meaning given above. Characteristic, Formula I (Wherein the ring with symbol C and X have the meaning of claim 1) A method for producing an ethylidene derivative of a tricyclic carbapenem.   14. A therapeutically effective amount of a formula in the form of an acid, a pharmaceutically acceptable salt or ester. An ethylidene derivative of the tricyclic carbapenem of I as an active ingredient; A pharmaceutical composition comprising a usual pharmaceutically acceptable carrier or auxiliary substance.   15． A therapeutically effective amount of a formula in the form of an acid, a pharmaceutically acceptable salt or ester. Ethylidene derivatives of tricyclic carbapenems of I and therapeutically effective amounts of β-lactams Contains an antibiotic as an active ingredient, and further contains a normal pharmaceutically acceptable carrier or A pharmaceutical composition comprising an auxiliary substance.   16． Tricyclic carbape of the formula I in the form of an acid, a pharmaceutically acceptable salt or an ester Prevention of bacterial infection in humans and animals with ethylidene derivatives of nem Use for treatment.   17． Tricyclic carbape of the formula I in the form of an acid, a pharmaceutically acceptable salt or an ester Β-lactamase, an enzyme in human and veterinary medicine, of an ethylidene derivative of nem Use as an inhibitor.   18． For use in preventing and treating bacterial infections in humans and animals A carbapenem of the formula I in the form of an acid, a pharmaceutically acceptable salt or an ester thereof, Ethylidene derivatives.   19. Use as inhibitor of the enzyme β-lactamase in human and veterinary medicine To form a tricyclic carbamate of the formula I in the form of an acid, a pharmaceutically acceptable salt or an ester. Ethylidene derivative of penem.